Factors Associated with Topical Medication Instillation Failure in Glaucoma: VRAMS-QPiG Study.

INTRODUCTION: To report eyedrop instillation techniques and factors associated with instillation failure among glaucoma subjects in the Video-Recorded Assessment of Medication Skill and Questionnaire-based evaluation of Perception in Glaucoma Study. METHODS: In this cross-sectional observational study, subjects were 60 patients with glaucoma (mean ± standard deviation age, 68.4 ± 11.3 years; 30 men) who required ocular hypotensive medication(s). Subjects completed ophthalmologic examinations and the Mini-Cog cognitive function test; their typical eyedrop instillation technique was video-recorded. Subjects rated their technique as successes/failures by questionnaire and two examiners rated the successes/failures based on video assessment. Discrepancy between self-reported and video-assessed success/failure rates of instillation was the main outcome measures. Multivariate logistic regression identified factors in instillation failure. RESULTS: Of 48/56 (86%) self-reported successes, 27/48 (56%) failed based on video assessment; as a result, 32/56 (57%) were inconsistent between subjective and objective assessments. Overall, 30/56 (54%) failed based on video assessment. In the subject-based data model, older age [odds ratio (OR) 0.93/year, P = 0.025] and lower cognitive function score (OR 2.7/score, P = 0.025) were factors in failed instillations. In the eye-based data model, less myopic objective refractive error (OR 0.77/diopter, P = 0.016) and lower visual field foveal threshold (OR 1.1/decibel, P = 0.041) were factors in failures. CONCLUSION: In addition to older age, decreased cognitive function, hyperopia, and decreased foveal sensitivity are risks for failed eyedrop instillation. Treating physicians can screen patients who require guidance by checking the risk factors of instillation failure rather than by relying on patient reports.

Efficacy and Safety of Omidenepag Isopropyl 0.002% Ophthalmic Solution: A Retrospective Analysis of Real-World Data in Japan.

INTRODUCTION: This study aimed to clarify the efficacy and safety of omidenepag isopropyl (OMDI) in a retrospective, real-world, multicenter setting. METHODS: A retrospective medical chart review of patients with glaucoma and ocular hypertension receiving OMDI from November 2018 to November 2019 with at least 12 weeks of follow-up was conducted in 11 eye clinics in Japan. The participants were categorized into three therapy groups, designated the naïve monotherapy, switching monotherapy, and concomitant therapy groups. The main outcome measures were the change in intraocular pressure (IOP) at week 4 and week 12 after the initiation of OMDI treatment, and frequency of adverse drug reactions. RESULTS: Data were collected from 827 patients. The baseline IOP in the naïve group was 16.6 ± 4.2 mmHg. The mean IOP reduction at week 4 and week 12 was - 2.9 ± 3.2 mmHg (P < 0.0001) and - 2.5 ± 2.9 mmHg (P < 0.0001), respectively. Eyes with baseline IOP less than 16 mmHg also showed a significant reduction of IOP of - 1.4 ± 2.0 mmHg at week 12. OMDI significantly reduced IOP not only in eyes with primary open-angle glaucoma but also in eyes with primary angle-closure glaucoma and secondary glaucoma. In the switching monotherapy group, IOP did not change significantly after switching from most classes of medications to OMDI, but further IOP reduction was observed in the case of switching from beta-blockers to OMDI. The frequency of adverse drug reactions was 14.1% in all participants, and the most common adverse reaction was ocular hyperemia (7.6%). No serious and severe side effects were observed in this study. CONCLUSION: OMDI showed an IOP-lowering effect in eyes with various types of glaucoma and using various therapeutic regimens in real-world clinical practice. In addition, OMDI did not show any serious and severe side effects, suggesting the potential of OMDI as a first-line medicine for the treatment of glaucoma. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN): 000040040.

Twenty-Four-Hour Intraocular Pressure Control with Omidenepag Isopropyl 0.002% in Patients with Glaucoma and Ocular Hypertension.

PURPOSE: To clarify the intraocular pressure (IOP)-lowering effect of a selective prostanoid EP2 receptor agonist, omidenepag isopropyl (OMDI) during a 24-hour period. PATIENTS AND METHODS: Subjects aged ≥20 years and with diagnosed, untreated primary open-angle glaucoma or ocular hypertension were enrolled. IOP measurements were performed every 4 hours over a 24-hour period using a Goldmann applanation tonometer (GAT) and Icare PRO tonometer (PRO). The baseline 24-hour IOP was measured in untreated subjects. After the baseline measurements, participants were given OMDI 1 drop once daily at night for 4 weeks. At week 4, the IOP measurement was repeated under the same conditions. Diurnal (9 am, 1 pm, 5 pm) and nocturnal (9 pm, 1 am, 5 am) IOP measurements were compared between baseline and treatment with OMDI. Safety measures included adverse events, slit-lamp biomicroscopy, visual acuity, heart rate and blood pressure. RESULTS: Of 27 participants enrolled, 25 patients (20 males and 5 females, average age 52.2 ± 8.5 years) completed the study. In the sitting position, the baseline diurnal and nocturnal mean IOPs (GAT) were 19.1 ± 2.1 mmHg and 18.2 ± 2.6 mmHg, respectively, the diurnal and nocturnal mean IOP reduction from baseline were -2.8 ± 2.6 mmHg (p < 0.0001) and -3.3 ± 2.9 mmHg (p < 0.0001), respectively, mean 24-hour IOP (GAT) was significantly lower with the OMDI treatment (-3.1 ± 2.5 mmHg, p < 0.0001). In the supine position, the baseline nocturnal mean IOP (PRO) was 17.99 ± 2.22 mmHg, and the nocturnal mean IOP reduction from baseline was -1.78 ± 2.37 mmHg (p = 0.0009) after 4 weeks of the treatment. Nine adverse events were observed in 8 patients including mild conjunctival hyperemia (n = 8) and mild iritis (n=1). There were no significant effects on systemic safety. CONCLUSION: Once daily OMDI treatment was able to produce stable 24-hour IOP reduction.

Inhibitory effects of cyclosporine a eye drops on symptoms in late phase and delayed-type reactions in allergic conjunctivitis models.

We investigated the efficacy of cyclosporine A (CyA) eye drops on ocular symptoms in late phase and delayed-type reactions in guinea pig allergic conjunctivitis models. An emulsion of ovalbumin (OVA) and Freund's complete adjuvant (FCA) was intraperitoneally injected into guinea pigs, and 15% OVA solution was applied topically to the eyes to elicit late phase reactions. Following the early phase reaction, increased scores for hyperemia, swelling, edema, and discharge were detected 6 h after antigen challenge, and CyA eye drops significantly inhibited the increase in scores for edema and discharge, the increase in the number of infiltrating inflammatory cells, and the percentage of eosinophils among polymorphonuclear leukocytes in conjunctival tissue. To induce delayed-type reactions, guinea pigs were sensitized by injecting FCA into the footpad, followed by injections of purified protein derivative into palpebral conjunctivae 24 d later. Increased scores for hyperemia, swelling, and discharge were detected 6 h after the induction of delayed-type allergy, and CyA eye drops significantly inhibited the increase in scores for hyperemia and swelling. In contrast, betamethasone sodium phosphate eye drops showed a tendency to inhibit the symptoms in both late phase and delayed-type reactions, or inflammatory cell infiltration in the late phase reaction, but the inhibition was not significant. These results suggest that CyA eye drops are useful for suppressing ocular symptoms in both late phase and delayed-type reactions in allergic conjunctivitis models.

Transfer of a T-helper type 2 clone into conjunctiva induces corneal damage in mice.

PURPOSE: We established a T-helper Type 2 (Th2) clone-induced conjunctival eosinophilia model by injecting D10.G.4.1 (D10) cells, a murine Th2 clone, and conalbumin, its specific antigen, into conjunctiva of AKR/J mice. Using this model, we investigated the effect of a coinjection of D10 cells and conalbumin into conjunctiva on corneal damage. METHODS: Corneal fluorescein staining scores and eosinophil peroxidase (EPO) activity in conjunctiva were measured after coinjection of D10 and conalbumin into conjunctiva, and the effects of cyclosporine A, betamethasone, and anti-interleukin-5 antibody on staining scores and EPO activity were examined. RESULTS: Coinjection of D10 and conalbumin induced an increase of the corneal fluorescein staining score after 24, 48, and 96 hours and 10 days. EPO activity in conjunctiva increased time-dependently until 24 hours after coinjection. The increase in the staining score followed the time dependent increase in EPO activity. The instillation of cyclosporine A, an inhibitor of cytokine production from T-cells, and betamethasone significantly inhibited the increase in corneal fluorescein score and EPO activity. Intraperitoneal administration of anti-interleukin-5 monoclonal antibody, which inhibits the infiltration of eosinophils into the conjunctiva, completely inhibited the increase in staining score. CONCLUSION: The transfer of the Th2 clone into the murine conjunctiva induced corneal damage, which may have been caused by Th2 cell-produced interleukin-5 that mediated the activation of eosinophils.

Cyclosporine A eye drops inhibit the early-phase reaction in a type-I allergic conjunctivitis model in mice.

PURPOSE: The effects of cyclosporine A eye drops on the early-phase reaction were investigated in a type-I allergic conjunctivitis model. METHODS: Mice were actively sensitized with ragweed (RW) absorbed on aluminium hydroxide gel and challenged with RW for 10 days (single challenge model) or 10-14 days (repetitive challenge model) after the first sensitization. For the evaluation of itching, ovalbumin was used as an antigen instead of RW. The effects of cyclosporine A eye drops on increased vascular permeability, mast cell degranulation, and itching were evaluated and compared with those of other anti-allergic eye drops. RESULTS: In the single challenge model, cyclosporine A eye drops significantly inhibited the increase in vascular permeability and histological evaluations showed suppressed degranulation of mast cells. Disodium cromoglycate (DSCG) eye drops showed only a slight tendency to inhibit the increase in both pathophysiological parameters. Ketotifen or betamethasone eye drops significantly inhibited the increase in vascular permeability. The order of potency in the single challenge model was ketotifen > cyclosporine A > betamethasone. In the repetitive challenge model, cyclosporine A eye drops significantly inhibited the increase in vascular permeability and DSCG eye drops showed only slight inhibition. Ketotifen or betamethasone significantly inhibited the increase in vascular permeability. The order of potency in the repetitive challenge model was cyclosporine A > betamethasone > ketotifen. The effect of cyclosporine A eye drops on the itch-scratch response was studied. Cyclosporine A and DSCG significantly reduced the itch-scratch response in the single and repetitive challenge models; the effect of cyclosporine A in the repetitive challenge model was more potent than in the single challenge model. CONCLUSIONS: Those results suggest that administration of cyclosporine A eye drops inhibit the early-phase reaction in type-I allergic conjunctivitis, which may be mediated by the suppression of mast cell degranulation. This action of cyclosporine A eye drops may be involved in the therapeutic effect of cyclosporine A on allergic conjunctivitis.

Cyclosporin A eye drops inhibit fibrosis and inflammatory cell infiltration in murine type I allergic conjunctivitis without affecting the early-phase reaction.

PURPOSE: To understand the mechanisms of action of cyclosporin A eye drops in severe allergic diseases such as vernal keratoconjunctivitis, the inhibitory effects of cyclosporin A eye drops on fibrosis and inflammatory cell infiltration in murine allergic conjunctivitis were evaluated. METHODS: BALB/c mice that had been actively sensitized with ovalbumin were challenged with ovalbumin on days 10-14 after initial sensitization. Cyclosporin A (0.1%) or betamethasone (0.1%) eye drops were instilled 1, 4, and 7 hours after each challenge. Ocular tissue was harvested for histological evaluation 24 hours after the last challenge, and conjunctival tissue was collected for the measurement of collagen content and quantitative PCR 8 hours after the last challenge. RESULTS: Scores for fibrosis and inflammatory cell infiltration and collagen content in the conjunctiva were higher after 5 days of antigen challenge than in normal non-challenged conjunctiva. Instillation of cyclosporin A or betamethasone reduced the antigen-induced increases in scores for fibrosis and inflammatory cell infiltration in the conjunctiva, and cyclosporin A significantly reduced the antigen-induced increase in conjunctival collagen content. Betamethasone also showed a tendency to reduce the increase in collagen content. Cyclosporin A and betamethasone decreased the numbers of CD3(+) and CD4(+) T-cells and eosinophils in the conjunctiva, but did not affect the number of mast cells. Neither type of eye drop suppressed the increase in vascular permeability that occurred for 30 minutes after the last antigen challenge. In quantitative PCR, cyclosporin A suppressed the expression of IL-4 and IL-5 mRNA but did not suppress the expression of transforming growth factor (TGF)-beta 1, whereas betamethasone suppressed the expression of IL-4, IL-5, and TGF-beta 1. CONCLUSION: The results suggest that cyclosporin A eye drops inhibited fibrosis and inflammatory cell infiltration by the suppression of Th2 cytokine production in repeatedly antigen-challenged conjunctiva without affecting the early-phase reaction.

Cryptomeria japonica-induced allergic conjunctivitis in mice.

Japanese cedar pollen (Cryptomeria japonica, Cry j) is the most common allergen causing pollinosis in Japan. However, short ragweed pollen is used commonly as the antigen for experimentally-induced allergic conjunctivitis (EC) and Cry j-induced EC in mice has not been published. We actively immunized BALB/c mice with Cry j, and then performed a challenge with eye drops containing Cry j. We evaluated the early phase and late phase reactions in the conjunctiva, using Evans blue dye leakage and eosinophil infiltration, respectively. Significant inhibition of the early phase reaction was observed following pre-challenge with eye drops that block histamine H1 receptor in the conjunctiva. Thus, Cry j-induced EC appears to represent a suitable model for the study of pollinosis in Japan.