Epinastine Cream: A Novel Once-Daily Therapeutic Agent for Allergic Conjunctivitis.

Purpose: To investigate the in vivo efficacy of epinastine cream in type I allergic models. Methods: The dose, timing, and antiallergic effect of epinastine cream on the conjunctiva were evaluated postapplication to the eyelid skin of guinea pigs with histamine- or ovalbumin-induced allergic conjunctivitis. Additionally, we assessed its antiallergic effects on the skin postapplication to the dorsal skin of guinea pigs with ovalbumin-induced passive cutaneous anaphylaxis. Efficacy was estimated by determining the amount of dye that leaked from conjunctival or dorsal skin tissue vessels as a measure of vascular permeability, scoring the severity of allergic symptoms, and observing the scratching behaviors using clinical parameters. Results: In the histamine-induced conjunctivitis model, epinastine cream strongly inhibited conjunctival vascular permeability in a dose-dependent manner. The inhibitory effect of 0.5% epinastine cream 24 h postapplication was significantly higher than that of 0.1% epinastine hydrochloride ophthalmic solution 8 h postadministration. Additionally, the 0.5% epinastine cream inhibited conjunctival vascular permeability 15 min postapplication, and the effect was sustained over 24 h. Furthermore, the 0.5% epinastine cream effectively suppressed clinical symptom scores and exhibited ameliorated scratching bouts in conjunctival allergic reactions in the experimental allergic conjunctivitis model. Additionally, it significantly inhibited vascular permeability in skin allergic reactions in the passive cutaneous anaphylaxis model. Conclusions: The results suggest that epinastine cream is a strong, long-lasting, and skin-penetrating inhibitor of type I allergic reactions. The 0.5% epinastine cream applied once daily could be a promising, potent, and long-acting therapeutic agent for allergic conjunctivitis.

Downregulation of COL12A1 and COL13A1 by a selective EP2 receptor agonist, omidenepag, in human trabecular meshwork cells.

Omidenepag isopropyl (OMDI) is an intraocular pressure (IOP)-lowering drug used to treat glaucoma. The active form of OMDI, omidenepag (OMD), lowers elevated IOP, the main risk factor for glaucoma, by increasing the aqueous humor outflow; however, a detailed understanding of this mechanism is lacking. To clarify the IOP-lowering mechanism of OMDI, the effects of OMD on the mRNA expression of the extracellular matrix, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) were evaluated in human trabecular meshwork cells. Under 2D culture conditions, the mRNA expression of FN1, COL1A1, COL1A2, COL12A1, and COL13A1 decreased in a concentration-dependent manner after 6 or 24 h treatment with 10 nM, 100 nM, and 1 µM OMD, while that of COL18A1 decreased after 6 h treatment with 1 µM OMD. Significant changes in expression were observed for many MMP and TIMP genes. Under 3D culture conditions, the extracellular matrix-related genes COL12A1 and COL13A1 were downregulated by OMD treatment at all three concentrations. Under both 2D and 3D culture conditions, COL12A1 and COL13A1 were downregulated following OMD treatment. Reduction in the extracellular matrix contributes to the decrease in outflow resistance, suggesting that the downregulation of the two related genes may be one of the factors influencing the IOP-lowering effect of OMDI. Our findings provide insights for the use of OMDI in clinical practice.

Tissue Reactivity to, and Stability of, Glaucoma Drainage Device Materials Placed Under Rabbit Conjunctiva.

Purpose: To evaluate tissue reactivity to, and the stability of, glaucoma drainage device materials placed under rabbit conjunctiva in vivo. Methods: Disks (diameter, 3 mm; thickness, ∼0.3 mm) fabricated from poly(styrene-block-isobutylene-block-styrene) (SIBS), silicone, stainless-steel, or glutaraldehyde cross-linked collagen (GACLC) were inserted under rabbit conjunctiva. Conjunctival and scleral sections obtained at 4, 8, and 12 weeks after surgery were immunostained for α-smooth muscle actin (SMA). The ratio of the maximum thickness of the α-SMA-positive conjunctiva to the scleral thickness (α-SMA/S ratio) was calculated. The in vivo stability of the drainage devices at 12 weeks after insertion was evaluated. Results: The mean α-SMA/S ratios of the SIBS and silicone groups were lower than that of the stainless-steel group at 4 weeks after surgery (P < 0.05), and that of the SIBS group was lower than that of the GACLC group (P < 0.05). The ratios at 8 weeks after surgery were lower in the SIBS and silicone groups than in the GACLC group (P < 0.01). The ratios at 12 weeks after surgery were lower in the SIBS and silicone groups than in the GACLC group (P < 0.05). The surface areas of GACLC disks explanted from conjunctivae were significantly lower than that of intact disks (P < 0.01). Conclusions: SIBS and silicon were highly biostable and exhibited less tissue reactivity than GACLC in vivo. Translational Relevance: Comparisons of materials using animal models can predict the clinical stability and safety of such materials in humans.

Intraocular Pressure-Lowering Effects of Trabeculectomy Versus MicroShunt Insertion in Rabbit Eyes.

Purpose: To compare the surgical results of PRESERFLO MicroShunt (MicroShunt) insertion and trabeculectomy in rabbit eyes. Methods: Trabeculectomy or MicroShunt insertion was performed on the eyes of Japanese white rabbits. Intraocular pressure (IOP) was measured on conscious rabbits using a rebound tonometer for up to 12 weeks after surgery. Filtering bleb appearance was evaluated. Scarring in the filtering bleb was assessed by immunohistochemical analyses. The change in mRNA expression in the conjunctiva was evaluated using RNA sequence analyses. Results: The preoperative IOP of the operative eye did not differ significantly between trabeculectomy (11.6 ± 1.0 mmHg, n = 10) and MicroShunt insertion (12.6 ± 1.3 mmHg, n = 10). In both groups, the IOP of the operative eye was significantly lower than that of the contralateral eye at one day postoperatively, which continued until 12 weeks after surgery. The peak differences in IOP were -8.4 ± 3.0 (trabeculectomy) and -8.1 ± 2.1 mmHg (MicroShunt) at two weeks after surgery; no significant differences were observed in IOP reduction between the groups. Appearance and immunohistochemical analyses of the filtering bleb showed no significant difference between the groups. Moreover, RNA sequence analysis results showed no difference between the groups in mRNA expression fluctuations. Conclusions: Postoperative IOP, bleb appearance, and immunohistochemical analysis results were similar in the trabeculectomy and MicroShunt groups, indicating that MicroShunt insertion is as effective as trabeculectomy in lowering IOP. Translational Relevance: Comparison of surgical procedures using animal models has made it possible to predict clinical efficacy and safety.

Additive Intraocular Pressure-Lowering Effects of a Novel Selective EP2 Receptor Agonist, Omidenepag Isopropyl, Combined with Existing Antiglaucoma Agents in Conscious Ocular Normotensive Monkeys.

Purpose: To investigate the intraocular pressure (IOP)-lowering effects of omidenepag isopropyl (OMDI), a potent and highly selective prostanoid EP2 receptor agonist, as a potential first-line ocular hypotensive agent when combined with existing antiglaucoma agents in conscious ocular normotensive monkeys. Methods: Male cynomolgus monkeys were examined under conscious conditions. OMDI ophthalmic solution alone was topically applied to an eye or combined with other ophthalmic solutions at 5-min intervals. The contralateral eye was left untreated. IOP was measured before and at 2, 4, 6, and 8 h after instillation. Results: Topical application of OMDI to the eye resulted in statistically significant IOP reduction, which lasted for at least 6 h. The IOP-lowering effects of OMDI concomitantly administered with any of the tested antiglaucoma agents (timolol, brinzolamide, netarsudil, ripasudil, and brimonidine) were greater than those of OMDI alone. Furthermore, these enhanced IOP responses to their concomitant use were statistically significant compared with those of the tested antiglaucoma agents alone. Any combination of OMDI with the tested agents did not lead to serious abnormalities either systemically or locally in the eye. Conclusions: We demonstrated that OMDI has additive IOP-lowering effects when administered in combination with various antiglaucoma agents, namely, ß-adrenergic antagonist, carbonic anhydrase inhibitor, Rho-associated coiled-coil containing protein kinase inhibitors, and α2-adrenergic agonist. These results suggest that OMDI provides additional clinical benefits because of its unique mechanisms of action when combination therapy is required.

Efficacy and safety of the fixed combinations of tafluprost/timolol and latanoprost/carteolol.

In this study, we made a comparative efficacy and safety assessment of two different fixed combinations of drugs, viz., tafluprost/timolol (TAF/TIM) and latanoprost/carteolol (LAT/CAR), by determining their effects on intraocular pressure (IOP) in ocular normotensive monkeys and examining their toxic effects on ocular surface using human corneal epithelial cells. TAF/TIM was found to be more effective in lowering IOP for a longer duration compared to LAT/CAR. We found that the difference in the intensity of IOP-lowering effect was because of the differences in the strength of timolol compared with that of carteolol as a beta-adrenergic antagonist and strength of tafluprost compared with that of latanoprost as a prostaglandin analogue. In addition, TAF/TIM showed much less cytotoxic effects compared to LAT/CAR on the human corneal epithelial cells. Our findings showed that TAF/TIM is better than LAT/CAR with regard to the IOP-lowering effect in monkeys and toxicity on ocular surface.

Beneficial pharmacological effects of selective glucocorticoid receptor agonist in external eye diseases.

PURPOSE: Glucocorticoids exert their actions via the glucocorticoid receptor through at least 2 intracellular mechanisms, known as transrepression and transactivation. It has been hypothesized that transrepression is the basis of their anti-inflammatory effects, whereas transactivation has been assumed to cause their side effects. ZK209614, a recently identified, novel selective glucocorticoid receptor agonist, exerts strong transrepression and weak transactivation. The objective of this study was to determine whether its pharmacological effects can be dissociated from its side effects. For this, we employed in vitro assays and topical in vivo models. METHODS: ZK209614 and dexamethasone were used in in vitro transrepression and transactivation assays. To evaluate anti-inflammatory and antiallergic activities in vivo, ZK209614 and betamethasone phosphate were tested in the carrageenan-induced conjunctivitis model and allergic conjunctivitis model in rats. To evaluate side effects in vivo, treatments with ZK209614 and betamethasone phosphate were tested for the ocular hypertensive effects in a feline model, each drug being administered topically. RESULTS: ZK209614 showed strong transrepression and weak transactivation in the in vitro assays. When given as eyedrops, ZK209614 and betamethasone phosphate each had an inhibitory effect on edema weight in the rat carrageenan-induced conjunctivitis model. In the rat allergic conjunctivitis model, ZK209614 reduced the elevated vascular permeability at a concentration of 0.1%. In the feline intraocular pressure (IOP)-elevation experiment, topically administered betamethasone phosphate elevated IOP, but ZK209614 had no effect on IOP. CONCLUSION: The present investigations suggest that ZK209614 eyedrops have both anti-inflammatory and antiallergic effects, but no unwanted IOP-elevating effect. On that basis, ZK209614 might be a promising candidate as an ophthalmic drug with a better therapeutic index than classic glucocorticoids.

Apafant, a potent platelet-activating factor antagonist, blocks eosinophil activation and is effective in the chronic phase of experimental allergic conjunctivitis in guinea pigs.

Platelet-activating factor (PAF) plays important roles in allergic reactions. In particular, there are many concerns about PAF, eosinophils, and the chronicity of allergic diseases. The purpose of the present studies is to elucidate the role of PAF in eosinophil activation at conjunctiva and to confirm the efficacy of Apafant (a potent PAF antagonist) ophthalmic solution in chronic experimental allergic conjunctivitis. Guinea pigs were actively immunized and allergic conjunctivitis was induced by repetitive instillation of 2.5% ovalbumin. PAF solution was topically applied and eosinophil activation was assessed by measuring the eosinophil peroxidase (EPO) activity in the tear fluid. Itch-scratching episodes and clinical symptoms scores were evaluated in the repetitive challenge conjunctivitis. From the instillation of PAF solution into guinea pig eyes, which were in a state of chronic allergic conjunctivitis, a significant increase in EPO activity was observed, and this increase was inhibited by pre-treatment with Apafant. In the repetitive challenge model, the animals treated with Apafant ophthalmic solution showed a significant reduction of clinical symptoms and the itch-scratch response in both the first and the second challenges. PAF has an activity, that induces mediator release from eosinophils in the conjunctival tissues and may be involved in the chronic phase of allergic conjunctivitis.

The role of platelet activating factor and the efficacy of apafant ophthalmic solution in experimental allergic conjunctivitis.

Platelet-activating factor (PAF) may be an important mediator in allergic conjunctivitis. In this study, apafant, a potent PAF antagonist, was evaluated for topical ocular anti-PAF activity in PAF and antigen stimulated conjunctivitis models. PAF, when injected into parpebral conjunctiva, provoked an acute increase, measured as dye leakage, in conjunctival vascular permeability. Apafant inhibited this response in a dose-related manner, and the inhibitory action of 0.1% apafant lasted for at least 6 hours duration. PAF, when instilled into the conjunctival sac, induced itch-scratching behavior and clinical symptoms, such as conjunctival redness and edema. These were inhibited by pretreatment with apafant ophthalmic solution. In a passive conjunctival anaphylaxis model in guinea pigs, significant inhibition of the allergic response was observed following topical ocular administration of apafant 5 and 15 minutes prior to the antigen challenge. We have demonstrated that PAF plays an important role in the development of allergic conjunctivitis. These results clearly indicate that apafant has potential as a topical ocular anti-PAF for treating allergic conjunctivitis.