P2Y receptors for extracellular nucleotides: Contributions to cancer progression and therapeutic implications.

Purinergic receptors for extracellular nucleotides and nucleosides contribute to a vast array of cellular and tissue functions, including cell proliferation, intracellular and transmembrane ion flux, immunomodulation and thrombosis. In mammals, the purinergic receptor system is composed of G protein-coupled P1 receptors A1, A2A, A2B and A3 for extracellular adenosine, P2X1-7 receptors that are ATP-gated ion channels and G protein-coupled P2Y1,2,4,6,11,12,13 and 14 receptors for extracellular ATP, ADP, UTP, UDP and/or UDP-glucose. Recent studies have implicated specific P2Y receptor subtypes in numerous oncogenic processes, including cancer tumorigenesis, metastasis and chemotherapeutic drug resistance, where G protein-mediated signaling cascades modulate intracellular ion concentrations and activate downstream protein kinases, Src family kinases as well as numerous mitogen-activated protein kinases. We are honored to contribute to this special issue dedicated to the founder of the field of purinergic signaling, Dr. Geoffrey Burnstock, by reviewing the diverse roles of P2Y receptors in the initiation, progression and metastasis of specific cancers with an emphasis on pharmacological and genetic strategies employed to delineate cell-specific and P2Y receptor subtype-specific responses that have been investigated using in vitro and in vivo cancer models. We further highlight bioinformatic and empirical evidence on P2Y receptor expression in human clinical specimens and cover clinical perspectives where P2Y receptor-targeting interventions may have therapeutic relevance to cancer treatment.

Molecular pharmacology of P2Y receptor subtypes.

Professor Geoffrey Burnstock proposed the concept of purinergic signaling via P1 and P2 receptors. P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular adenine and uracil nucleotides. Eight mammalian P2Y receptor subtypes have been identified. They are divided into two subgroups (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11) and (P2Y12, P2Y13, and P2Y14). P2Y receptors are found in almost all cells and mediate responses in physiology and pathophysiology including pain and inflammation. The antagonism of platelet P2Y12 receptors by cangrelor, ticagrelor or active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel reduces the ADP-induced platelet aggregation in patients with thrombotic complications of vascular diseases. The nucleotide agonist diquafosol acting at P2Y2 receptors is used for the treatment of the dry eye syndrome. Structural information obtained by crystallography of the human P2Y1 and P2Y12 receptor proteins, site-directed mutagenesis and molecular modeling will facilitate the rational design of novel selective drugs.

Context-Specific Switch from Anti- to Pro-epileptogenic Function of the P2Y1 Receptor in Experimental Epilepsy.

Extracellular ATP activates inflammatory responses to tissue injury. It is also implicated in establishing lasting network hyperexcitability in the brain by acting upon independent receptor systems. Whereas the fast-acting P2X channels have well-established roles driving neuroinflammation and increasing hyperexcitability, the slower-acting metabotropic P2Y receptors have received much less attention. Recent studies of P2Y1 receptor function in seizures and epilepsy have produced contradictory results, suggesting that the role of this receptor during seizure pathology may be highly sensitive to context. Here, by using male mice, we demonstrate that the metabotropic P2Y1 receptor mediates either proconvulsive or anticonvulsive responses, dependent on the time point of activation in relation to the induction of status epilepticus. P2Y1 deficiency or a P2Y1 antagonist (MRS2500) administered before a chemoconvulsant, exacerbates epileptiform activity, whereas a P2Y1 agonist (MRS2365) administered at this time point is anticonvulsant. When these drugs are administered after the onset of status epilepticus, however, their effect on seizure severity is reversed, with the antagonist now anticonvulsant and the agonist proconvulsant. This result was consistent across two different mouse models of status epilepticus (intra-amygdala kainic acid and intraperitoneal pilocarpine). Pharmacologic P2Y1 blockade during status epilepticus reduces also associated brain damage, delays the development of epilepsy and, when applied during epilepsy, suppresses spontaneous seizures, in mice. Our data show a context-specific role for P2Y1 during seizure pathology and demonstrate that blocking P2Y1 after status epilepticus and during epilepsy has potent anticonvulsive effects, suggesting that P2Y1 may be a novel candidate for the treatment of drug-refractory status epilepticus and epilepsy.SIGNIFICANCE STATEMENT This is the first study to fully characterize the contribution of a metabotropic purinergic P2Y receptor during acute seizures and epilepsy. The findings suggest that targeting P2Y1 may offer a potential novel treatment strategy for drug-refractory status epilepticus and epilepsy. Our data demonstrate a context-specific role of P2Y1 activation during seizures, switching from a proconvulsive to an anticonvulsive role depending on physiopathological context. Thus, our study provides a possible explanation for seemingly conflicting results obtained between studies of different brain diseases where P2Y1 targeting has been proposed as a potential treatment strategy and highlights that the timing of pharmacological interventions is of critical importance to the understanding of how receptors contribute to the generation of seizures and the development of epilepsy.

Limitación de la aplicación de las puntuaciones de riesgo en la clínica: la importancia de la validación / Limitations of current risk scoring in real world populations: the importance of external validation

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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.

Effect of diquafosol three per cent ophthalmic solution on tear film and corneal aberrations after cataract surgery.

BACKGROUND: The aim was to evaluate the effect of diquafosol on tear film parameters and corneal aberrations after cataract surgery. METHODS: This retrospective, comparative, observational case series included patients who underwent cataract surgery with or without peri-operative use of diquafosol three per cent ophthalmic solution. Patients in group I (31 eyes) were treated with diquafosol three per cent ophthalmic solution six times a day from one week before surgery to three months after surgery. Patients in group II (33 eyes) underwent cataract surgery without being administered diquafosol. Tear film break-up time (BUT), the ocular surface disease index (OSDI), the Oxford Scheme score, Schirmer's test I and corneal aberrations were determined before and at one and three months post-surgery. RESULTS: In group I, the BUT, OSDI and Oxford Scheme score showed significant improvement at one and three months post-surgery (p = 0.002 for BUT at one month and three months, p = 0.023 and p = 0.049 for OSDI at one month and three months and p = 0.001 and p = 0.026 for Oxford Scheme at one month and three months), compared to baseline. In group II, the BUT, OSDI and Oxford Scheme score did not show any significant improvement during the follow-up period. In both groups, Schirmer's test I significantly decreased at three months post-surgery (p = 0.011 for group I and p = 0.034 for group II), compared to baseline. There were significant differences in the BUT and OSDI between the groups at three months post-surgery (p = 0.037 for BUT and p = 0.011 for OSDI). Regarding the corneal aberration, there were no significant differences between the groups at three months post-surgery. CONCLUSION: Peri-operative application of diquafosol three per cent ophthalmic solution may prevent dry eye-related ocular surface changes accompanied by improvement of ocular symptom. No definite changes in corneal aberrations were noted.

Influence of Ophthalmic Solutions on Tear Components.

Tear fluids are a mixture of secretions derived from lacrimal glands, accessory lacrimal glands, conjunctiva, and meibomian glands. Compositional changes to tears occur in the normal state and during ocular surface disease, such as dry eye conditions. We have investigated compositional changes to tears after topical application of ophthalmic solutions, with regard to tear-specific proteins (secretory immunoglobulin A, lactoferrin, lipocalin-1, and lysozyme) and ocular surface mucin in normal and dry eye conditions using high-performance liquid chromatography. After application of saline solution (0.9% sodium chloride) in normal subjects, transient but significant decreases in all tear components were observed. The recovery of protein concentrations took up to 30 minutes and lasted longer when the saline solution was applied more frequently. When applying ophthalmic solutions, a balance between washout and dilutional effects should be considered in addition to the therapeutic effect. Investigation of the effect of diquafosol solution (3%) in normal subjects revealed a significant increase in sialic acid concentration, a marker of ocular mucin, at 5 minutes after application, whereas a significant decrease was observed with saline. This result indicates the accelerated secretion of mucin from ocular tissues induced by diquafosol. A clinical study to determine the efficacy of diquafosol in patients with dry eye revealed improvements in tear breakup time, keratoconjunctival staining scores, and Schirmer test score, accompanied by an increase in sialic acid concentration in tears. Investigating normal and dry eye conditions through tear analysis may clarify the pathophysiology of dry eye conditions and support the efficacy of treatments.

The increase of aqueous tear volume by diquafosol sodium in dry-eye patients with Sjögren's syndrome: a pilot study.

PurposeTo investigate the effect of 3% diquafosol sodium ophthalmic solution (DQS) on aqueous tear volume increase in dry-eye patients with Sjögren's syndrome (SS).MethodsIn this pilot study, 17 dry-eye patients with SS (1 male and 16 females; mean age: 66.4 years) were enrolled and underwent topical instillation of two ophthalmic solutions, artificial tears (AT) in one eye and DQS in the fellow eye, in a masked manner. The central lower tear meniscus radius (TMR) curvature was measured before and at 15 min after instillation by video-meniscometry. Simultaneously, all patients self-evaluated their symptoms of wetness and stinging using a visual analog scale (VAS, in millimeters).ResultsTopical instillation of DQS significantly increased the TMR at 15 min (mean: 0.21±0.08 (SD) mm) compared with at baseline (mean: 0.16±0.07 mm) (P<0.001, paired t-test), whereas AT had no effect at baseline (mean: 0.18±0.09 mm) or at 15 min (mean: 0.18±0.09 mm). The visual VAS score of wetness at 15-min post-instillation increased in both groups compared with at baseline. In the DQS-treated eyes, the post-instillation change in TMR from baseline was not correlated with the baseline value of the Schirmer test, corneal staining score, or conjunctival staining score.ConclusionsTopical instillation of DQS increased aqueous tear volume on the ocular surface of dry-eye patients with SS, with its action being independent of lacrimal gland function.

Antiplatelet efficacy of P2Y12 inhibitors (prasugrel, ticagrelor, clopidogrel) in patients treated with mild therapeutic hypothermia after cardiac arrest due to acute myocardial infarction.

Survivors after cardiac arrest (CA) due to AMI undergo PCI and then receive dual antiplatelet therapy. Mild therapeutic hypothermia (MTH) is recommended for unconscious patients after CA to improve neurological outcomes. MTH can attenuate the effectiveness of P2Y12 inhibitors by reducing gastrointestinal absorption and metabolic activation. The combined effect of these conditions on the efficacy of P2Y12 inhibitors is unknown. We compared the antiplatelet efficacies of new P2Y12 inhibitors in AMI patients after CA treated with MTH. Forty patients after CA for AMI treated with MTH and received one P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) were enrolled in a prospective observational single-center study. Platelet inhibition was measured by VASP (PRI) on days 1, 2, and 3 after drug administration. In-hospital clinical data and 1-year survival data were obtained. The proportion of patients with ineffective platelet inhibition (PRI > 50 %, high on-treatment platelet reactivity) for clopidogrel, prasugrel, and ticagrelor was 77 vs. 19 vs. 1 % on day 1; 77 vs. 17 vs. 0 % on day 2; and 85 vs. 6 vs. 0 % on day 3 (P < 0.001). The platelet inhibition was significantly worse in clopidogrel group than in prasugrel or ticagrelor group. Prasugrel and ticagrelor are very effective for platelet inhibition in patients treated with MTH after CA due to AMI, but clopidogrel is not. Using prasugrel or ticagrelor seems to be a more suitable option in this high-risk group of acute patients.

Clinical Effects and Safety of 3% Diquafosol Ophthalmic Solution for Patients With Dry Eye After Cataract Surgery: A Randomized Controlled Trial.

PURPOSE: To compare the efficacies and safety profiles of 3% diquafosol and 0.1% sodium hyaluronate in patients with dry eye after cataract surgery. DESIGN: Randomized controlled trial. METHODS: setting: Soonchunhyang University Hospital, Seoul, South Korea. STUDY POPULATION: In all, 130 eyes of 86 dry eye patients who had undergone cataract surgery between January 2014 and January 2015 were enrolled and randomly divided into a diquafosol group and a sodium hyaluronate group. INTERVENTION: The diquafosol group used diquafosol 6 times a day and the hyaluronate group used sodium hyaluronate 6 times a day after cataract surgery. MAIN OUTCOME MEASURES: Evaluations of efficacy were conducted based on an Ocular Surface Disease Index questionnaire, tear breakup time (TBUT), Schirmer I test, corneal fluorescein and conjunctival lissamine green staining scores, serial measurement of ocular higher-order aberrations (HOAs), corneal HOAs, and uncorrected distance visual acuity test. Safety evaluations were based on anterior chamber inflammation and discontinuation of the eye drops. RESULTS: Objective signs and subjective symptoms were aggravated at 1 week postoperatively and began to recover significantly 4 weeks after surgery. The diquafosol group showed significantly superior TBUT (P < .001), corneal fluorescein (P = .045), and conjunctival staining (P = .001) compared to the sodium hyaluronate group throughout the study period. TBUT (P < .001) and the change in HOAs (P = .018) recovered significantly more quickly in the diquafosol group. The safety evaluations showed no intergroup differences. CONCLUSIONS: Eye drops of 3% diquafosol may be an effective and safe treatment for the management of cataract surgery-induced dry eye aggravation in patients with preexisting dry eye.

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.

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.

Efficacy and safety of topical diquafosol ophthalmic solution for treatment of dry eye: a systematic review of randomized clinical trials.

PURPOSE: To evaluate the efficacy and safety of topical diquafosol ophthalmic solution for treatment of dry eye. METHODS: Randomized clinical trials (RCTs) from MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were identified to evaluate the efficacy and safety of topical administration of diquafosol to patients with dry eyes. Data evaluation was based on endpoints including Schirmer test, tear film break-up time, ocular surface staining score, subjective symptom score, and adverse events. RESULTS: A total of 8 RCTs involving 1516 patients were selected based on the prespecified criteria. Significant improvement of Schirmer test values and tear film break-up time were reported in 40% (2 of 5) and 80% (4 of 5) studies, respectively. Ocular surface staining scores significantly decreased in 100% (fluorescein corneal staining, 6 of 6; Rose Bengal corneal and conjunctival staining, 4 of 4) RCTs. Symptoms significantly improved in 75% (6 of 8) RCTs in patients with dry eyes. No severe adverse events were reported with the concentration of diquafosol from 0.5% to 5%. Heterogeneity in study design prevented meta-analysis from statistical integration and summarization. CONCLUSIONS: Topical diquafosol seems to be a safe therapeutic option for the treatment of dry eye. The high variability of the selected RCTs compromised the strength of evidence and limits the determination of efficacy. However, the topical administration of diquafosol seems to be beneficial in improving the integrity of the epithelial cell layer of the ocular surface and mucin secretion in patients with dry eyes. This review indicates a need for standardized criteria and methods for evaluation to assess the efficacy of diquafosol in the future clinical trials.

Intraocular Scattering after Instillation of Diquafosol Ophthalmic Solution.

PURPOSE: To assess the changes in intraocular scattering before and after instillation of diquafosol ophthalmic solution in patients with short tear breakup time (TBUT) dry eye. METHODS: We prospectively examined 20 eyes of 20 short TBUT dry eye patients (study group) and age-matched 20 eyes of 20 healthy subjects (control group). Intraocular scattering was measured as the objective scattering index (OSI) at 0.5-second intervals over 10 seconds without blinking. Patients were instructed to start topical administration of 3% diquafosol ophthalmic solution six times daily for 4 weeks. RESULTS: The OSI significantly deteriorated after 7.0 seconds compared with the initial value of OSI after the blinking in the study group. The OSI was also significantly higher in the study group than in the control group at 4.5 to 10.0 seconds after the blinking (p < 0.05). We found significant improvements 2 weeks after treatment not only in TBUT (p < 0.001) but also in the mean OSI, the OSI change rate, and the slope of the linear regression line of the OSI within 10 seconds (p < 0.001, p = 0.003, and p = 0.002, respectively). We also found significant improvements 4 weeks after treatment in these variables. CONCLUSIONS: Intraocular scattering deteriorates significantly with time in patients with short TBUT dry eye. Diquafosol ophthalmic solution exhibits an improvement not only in TBUT but also in intraocular scattering, indicating that diquafosol is also effective for improving the optical quality of the eye.

Clinical usefulness of diquafosol for real-world dry eye patients: a prospective, open-label, non-interventional, observational study.

INTRODUCTION: This study was designed to evaluate the efficacy and safety of 3% diquafosol ophthalmic solution in dry eye patients in clinical practice. METHODS: Subjects were dry eye patients who had never used diquafosol, and observation was conducted prospectively over 2 months. The corneal and conjunctival fluorescein staining score, tear film break-up time, 12 dry eye-related subjective symptoms, patient-reported outcomes, and adverse events were investigated. RESULTS: Data were collected from 465 medical institutions for 3,196 patients. Diquafosol led to significant improvement in all subjective symptoms and objective findings (P < 0.001, paired t test). Diquafosol was effective regardless of the degree of severity according to the corneal and conjunctival fluorescein staining score or therapeutic pattern. Overall, 76.0% patients responded that their condition had improved. Adverse reactions were observed in 6.3% of patients. The major adverse reactions were eye discharge, eye irritation, and eye pain. CONCLUSION: Diquafosol was effective for various dry eye patients in clinical practice, and no significant safety-related problems occurred.

Effects of topical diquafosol pretreatment on intraoperative corneal wetting.

PURPOSE: To examine the effects of pretreatment with diquafosol 3.0% ophthalmic solution on corneal surface wetting during cataract surgery with intraocular lens (IOL) implantation in cases of senile cataract. SETTING: Shohzankai Medical Foundation, Miyake Eye Hospital, Nagoya, Japan. DESIGN: Prospective randomized single-masked comparative study. METHODS: Phacoemulsification and IOL implantation were performed in eyes with senile cataract. After a 2-week washout period, patients were randomly assigned to receive 1 drop of diquafosol 3.0% ophthalmic solution or artificial tears 6 times daily for 4 weeks before surgery. The main outcome measure, termed the corneal wetting property, was the time between when a clear image of the operating microscope light source appeared just after the corneal surface was irrigated with a balanced salt solution and the time at which that image began to blur. RESULTS: The study enrolled 51 patients (76 eyes). The mean time to corneal wetting was 50.1 seconds ± 10.8 (SD) in the diquafosol group and 45.3 ± 9.2 seconds in the artificial tears group. The difference between the 2 groups was statistically significant (P<.029). CONCLUSION: Four-week pretreatment with diquafosol 3.0% ophthalmic solution in patients with senile cataract scheduled for cataract surgery with IOL implantation was effective in enhancing the intraoperative corneal surface wetting property, which suggests improved optical clarity during surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Effect of rebamipide ophthalmic suspension on signs and symptoms of keratoconjunctivitis sicca in Sjögren syndrome patients with or without punctal occlusions.

PURPOSE: The aim of this study was to investigate the efficacy of 2% rebamipide suspension in treatment of keratoconjunctivitis sicca (KCS) in patients with Sjögren syndrome (SS) with or without punctal occlusions. METHODS: Thirty patients with SS, diagnosed based on the presence of autoantibodies and/or focus score >1 on lip biopsies, with corneal fluorescein staining scores (FSS) >3, and conjunctival lissamine green-staining scores (LSS) >3, were treated 4 times daily for 4 weeks with 2% rebamipide ocular suspension. Ocular examinations were performed before treatment and 2 and 4 weeks after treatment to evaluate FSS (0-9), LSS (0-6), and tear film break-up time (BUT). Hyaluronate and/or artificial tears were not discontinued. The patients were interviewed regarding the 5 major KCS symptoms, foreign body sensation, dry eye sensation, photophobia, ocular pain, and blurred vision, with each graded from none (0) to very severe (4). RESULTS: Of the 30 patients, 3 failed to attend all sessions, leaving 27 (25 females, 2 males, mean age 62.5 ± 10.8 years) to be studied. FSS and LSS showed improvement at week 2, but BUT showed improvement later, at week 4. All 5 symptoms improved significantly. When the patients were divided into 3 groups according to the presence of punctal occlusions, FSS and LSS were found to improve in all groups, but BUT improved only in patients with both puncta occluded at week 4. CONCLUSIONS: Rebamipide ophthalmic suspension was effective in treating KCS of patients with SS, probably by increasing mucins and suppressing inflammatory cytokines. Punctal occlusions resulted in sufficient retention of tear fluid to enhance the activities of rebamipide and improve BUT.

Effect of diquafosol tetrasodium eye drop for persistent dry eye after laser in situ keratomileusis.

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.

Facilitation of tear fluid secretion by 3% diquafosol ophthalmic solution in normal human eyes.

PURPOSE: To evaluate the increase in tear fluid volume induced by 3% diquafosol ophthalmic solution in normal human eyes. DESIGN: Prospective, randomized, double-masked, comparative study. METHODS: Twenty healthy adults (17 males and 3 females; mean age, 38.8 years) underwent topical instillation of 2 ophthalmic solutions, artificial tears in 1 eye and 3% diquafosol ophthalmic solution in the fellow eye, in a masked manner. The radius of curvature of the central lower tear meniscus was measured at 5, 10, 15, 30, and 60 minutes after instillation by use of reflective meniscometry, and subjects' self-evaluated symptoms of wetness and stinging using a visual analog scale. RESULTS: Changes after instillation in the radius of curvature from baseline (artificial tear group vs diquafosol group; mean ± standard error of the mean) were as follows: at 5 minutes, -0.008 ± 0.012 vs 0.045 ± 0.013; at 10 minutes, 0.001 ± 0.014 vs 0.057 ± 0.016; at 15 minutes, -0.012 ± 0.014 vs 0.037 ± 0.019; at 30 minutes, -0.010 ± 0.016 vs 0.030 ± 0.025; and at 60 minutes, -0.029 ± 0.012 vs -0.020 ± 0.012. The diquafosol group showed significantly greater values from 5 to 30 minutes after instillation. Of the 40 eyes, 13 showed abnormal tear film breakup time (≤5 seconds). The diquafosol group had significantly more wetness at 15 minutes after instillation than did the artificial tear group. CONCLUSIONS: Topical instillation of 3% diquafosol ophthalmic solution increases tear fluid on the ocular surface for up to 30 minutes in normal human eyes.

P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo.

Extracellular nucleotides acting via P2 receptors play important roles in cardiovascular physiology/pathophysiology. Pyrimidine nucleotides activate four G protein-coupled P2Y receptors (P2YRs): P2Y2 and P2Y4 (UTP-activated), P2Y6, and P2Y14. Previously, we showed that uridine 5'-triphosphate (UTP) activating P2Y2R reduced infarct size and improved mouse heart function after myocardial infarct (MI). Here, we examined the cardioprotective role of P2Y2R in vitro and in vivo following MI using uridine-5'-tetraphosphate δ-phenyl ester tetrasodium salt (MRS2768), a selective and more stable P2Y2R agonist. Cultured rat cardiomyocytes pretreated with MRS2768 displayed protection from hypoxia [as revealed by lactate dehydrogenase (LDH) release and propidium iodide (PI) binding], which was reduced by P2Y2R antagonist, AR-C118925 (5-((5-(2,8-dimethyl-5H-dibenzo[a,d][7]annulen-5-yl)-2-oxo-4-thioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(1H-tetrazol-5-yl)furan-2-carboxamide). In vivo, echocardiography and infarct size staining of triphenyltetrazolium chloride (TTC) in 3 groups of mice 24 h post-MI: sham, MI, and MI+MRS2768 indicated protection. Fractional shortening (FS) was higher in MRS2768-treated mice than in MI alone (40.0 ± 3.1 % vs. 33.4 ± 2.7 %, p < 0.001). Troponin T and tumor necrosis factor-α (TNF-α) measurements demonstrated that MRS2768 pretreatment reduced myocardial damage (p < 0.05) and c-Jun phosphorylation increased. Thus, P2Y2R activation protects cardiomyocytes from hypoxia in vitro and reduces post-ischemic myocardial damage in vivo.