Suprachoroidal Injection of Triamcinolone Acetonide Suspension: Ocular Pharmacokinetics and Distribution in Rabbits Demonstrates High and Durable Levels in the Chorioretina.

To compare ocular pharmacokinetics (PK), systemic absorption, and injectability of triamcinolone acetonide (TA) suprachoroidal (SC) and intravitreal (IVT) suspensions. New Zealand White (NZW) rabbits received a bilateral injection of 4 mg TA injectable suspension, TRI (TRIESENCE ; Alcon) through either microneedle-based SC or standard IVT injection. Another group of NZW rabbits received a bilateral SC injection (4 mg) of either TRI or a proprietary TA suspension for SC use, CLS-TA (Clearside Biomedical).

Dose Uniformity of Loteprednol Etabonate (Submicron) Ophthalmic Gel 0.38% Compared with Prednisolone Acetate Ophthalmic Suspension 1.

Introduction: Loteprednol etabonate (submicron) ophthalmic gel 0.38% (LE SM gel 0.38%) is a corticosteroid formulation designed to retain the nonsettling characteristics of loteprednol etabonate ophthalmic gel 0.

Loteprednol etabonate (submicron) ophthalmic gel 0.38% dosed three times daily following cataract surgery: integrated analysis of two Phase III clinical studies.

Purpose: To evaluate the efficacy and safety of a submicron formulation of loteprednol etabonate (LE) gel 0.38% instilled three times daily (TID) compared with vehicle for the treatment of inflammation and pain following cataract surgery with intraocular lens implantation, integrated across two multicenter, double-masked, randomized, parallel-group, Phase III studies.

Patients And Methods: Subjects ≥18 years of age with anterior chamber (AC) cells ≥grade 2 (6-15 cells) on day 1 after cataract surgery were randomized to receive 1 drop of LE gel 0.

Rheological Properties, Dissolution Kinetics, and Ocular Pharmacokinetics of Loteprednol Etabonate (Submicron) Ophthalmic Gel 0.38.

To evaluate rheological properties, dissolution, and ocular pharmacokinetics of loteprednol etabonate (LE) (submicron) ophthalmic gel 0.38%. The viscosity of the LE gel 0.

Bepotastine besilate ophthalmic solution 1.5% for alleviating nasal symptoms in patients with allergic conjunctivitis.

Background: Bepotastine besilate ophthalmic solution (BBOS) 1.5% is a topical antihistamine for the treatment of ocular itching associated with allergic conjunctivitis (AC). Allergic rhinitis and AC are common comorbid conditions.

Brimonidine Ophthalmic Solution 0.025% for Reduction of Ocular Redness: A Randomized Clinical Trial.

Significance: The α2-adrenergic receptor agonist brimonidine has been reported to induce conjunctival blanching in cataract, strabismus, laser refractive, and filtration procedures. Clinicians are often faced with red eyes with no apparent underlying pathology. Low-dose brimonidine reduced ocular redness in such subjects with efficacy maintained over 1 month and negligible rebound redness.

The Role of Nitric Oxide in the Intraocular Pressure Lowering Efficacy of Latanoprostene Bunod: Review of Nonclinical Studies.

Latanoprostene bunod (LBN) is a topical ophthalmic therapeutic for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension (OHT). LBN is composed of latanoprost acid (LA) linked to a nitric oxide (NO)-donating moiety and is the first NO-releasing prostaglandin analog to be submitted for marketing authorization in the United States. The role of latanoprost in increasing uveoscleral outflow of aqueous humor (AqH) is well established.

Impact of the Topical Ophthalmic Corticosteroid Loteprednol Etabonate on Intraocular Pressure.

Corticosteroids are a mainstay therapeutic option for the treatment of ocular inflammation. However, safety remains a concern for clinicians, particularly with long-term use. Though highly effective at suppressing inflammatory and allergic responses, topical ophthalmic corticosteroids carry an inherent risk of side effects, including elevated intraocular pressure (IOP), a risk factor for the development of glaucoma.

Regulation of Endothelin-1-Induced Trabecular Meshwork Cell Contractility by Latanoprostene Bunod.

Purpose: Previous in vivo studies demonstrated that latanoprostene bunod (LBN), a nitric oxide (NO)-donating prostaglandin F2α receptor agonist, results in greater intraocular pressure (IOP) lowering than latanoprost. The present series of investigations compared the effects of LBN and latanoprost on primary human trabecular meshwork cell (HTMC) contractility and underlying signaling pathways to determine whether LBN might mediate this additional IOP lowering via the conventional outflow pathway.

Methods: The effect of LBN (1-100 μM) on HTMC cGMP levels was determined by ELISA with or without the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ).

Mapracorat, a selective glucocorticoid receptor agonist, upregulates RelB, an anti-inflammatory nuclear factor-kappaB protein, in human ocular cells.

Selective glucocorticoid receptor agonists (SEGRAs) are a new class of compounds under clinical evaluation for treatment of ocular inflammation. Widely prescribed therapeutics, such as glucocorticoids, are effective at reducing ocular inflammation, but their long term use predisposes to undesirable side effects. The purpose of this study was to investigate a novel SEGRA, mapracorat (BOL-303242-X), and the differences in mapracorat's mechanism of action compared with traditional steroids (i.

Nitric oxide (NO): an emerging target for the treatment of glaucoma.

The predominant risk factor for the progression of glaucoma is an increase in IOP, mediated via a reduction in aqueous outflow through the conventional (trabecular meshwork and Schlemm's canal) outflow pathway. Current IOP lowering pharmacological strategies target the uveoscleral (nonconventional) outflow pathway or aqueous humor production; however, to date no therapy that primarily targets the conventional pathway exists. Nitric oxide (NO) is an intracellular signaling molecule produced by endogenous NO synthases, well-known for its key role in vasodilation, through its action on smooth muscle cells.

Mapracorat, a selective glucocorticoid receptor agonist, causes apoptosis of eosinophils infiltrating the conjunctiva in late-phase experimental ocular allergy.

Background: Mapracorat, a novel nonsteroidal selective glucocorticoid receptor agonist, has been proposed for the topical treatment of inflammatory disorders as it binds with high affinity and selectivity to the human glucocorticoid receptor and displays a potent anti-inflammatory activity, but seems to be less effective in transactivation of a number of genes, resulting in a lower potential for side effects. Contrary to classical glucocorticoids, mapracorat displays a reduced ability to increase intraocular pressure and in inducing myocilin, a protein linked to intraocular pressure elevation. Allergic conjunctivitis is the most common form of ocular allergy and can be divided into an early phase, developing immediately after allergen exposure and driven primarily by mast cell degranulation, and a late phase, developing from 6-10 hours after the antigen challenge, and characterized by conjunctival infiltration of eosinophils and other immune cells as well as by the production of cytokines and chemokines.

Anti-allergic effects of mapracorat, a novel selective glucocorticoid receptor agonist, in human conjunctival fibroblasts and epithelial cells.

Purpose: To determine the ocular anti-allergic effects of mapracorat, a novel selective glucocorticoid receptor agonist (SEGRA) in primary human conjunctival fibroblasts and epithelial cells.

Methods: Two primary human conjunctival cell types, human conjunctival epithelial cells (HConEpiC) and human conjunctival fibroblasts (HConF), were challenged with interleukin-4 (IL-4) or IL-13 plus tumor necrosis factor-alpha (TNF-α). Luminex technology was used to profile the resulting inflammatory response.

Anti-inflammatory and anti-oxidative effects of the green tea polyphenol epigallocatechin gallate in human corneal epithelial cells.

Purpose: To determine the anti-inflammatory and anti-oxidant effects of epigallocatechin gallate (EGCG), the major polyphenol component of green tea, in human corneal epithelial cells (HCEpiC).

Methods: HCEpiC were challenged with interleukin-1β (IL-1β) for 18 h or hyperosmolarity (440 mOsm) for 24 h. Luminex technology was used to determine the effects of EGCG (0.

Nonclinical safety evaluation of boric acid and a novel borate-buffered contact lens multi-purpose solution, Biotrue™ multi-purpose solution.

Multipurpose solutions (MPS) often contain low concentrations of boric acid as a buffering agent. Limited published literature has suggested that boric acid and borate-buffered MPS may alter the corneal epithelium; an effect attributed to cytotoxicity induced by boric acid. However, this claim has not been substantiated.

Mapracorat, a novel selective glucocorticoid receptor agonist, inhibits hyperosmolar-induced cytokine release and MAPK pathways in human corneal epithelial cells.

Purpose: Increasing evidence suggests that tear hyperosmolarity is a central mechanism causing ocular surface inflammation and damage in dry eye disease. Mapracorat (BOL-303242-X) is a novel glucocorticoid receptor agonist currently under clinical evaluation for use in the treatment of dry eye disease. This study assessed the anti-inflammatory effects of mapracorat in an in vitro osmotic stress model which mimics some of the pathophysiological changes seen in dry eye.

Gas6-Axl pathway: the role of redox-dependent association of Axl with nonmuscle myosin IIB.

In vascular smooth muscle cells, Axl is a key receptor tyrosine kinase, because it is upregulated in injury, increases migration and neointima formation, and is activated by reactive oxygen species. Reaction of glutathione with cysteine residues (termed "glutathiolation") is an important posttranslational redox modification that may alter protein activity and protein-protein interactions. To investigate the mechanisms by which reactive oxygen species increase Axl-dependent vascular smooth muscle cell function we assayed for glutathiolated proteins that associated with Axl in a redox-dependent manner.

BOL-303242-X, a novel selective glucocorticoid receptor agonist, with full anti-inflammatory properties in human ocular cells.

Purpose: BOL-303242-X is a novel selective glucocorticoid receptor agonist under clinical evaluation for the treatment of inflammatory skin and eye diseases. Data from in vitro and in vivo studies suggest an improved side-effect profile of this compound compared to classical glucocorticoids. The aim of this study was to determine the anti-inflammatory effect of BOL-303242-X in ocular cells.

Reduced myocilin expression in cultured monkey trabecular meshwork cells induced by a selective glucocorticoid receptor agonist: comparison with steroids.

Purpose: To assess in vitro myocilin (MYOC) expression in trabecular meshwork (TM) cells exposed to BOL-303242-X, a selective glucocorticoid receptor (GR) agonist (SEGRA), in comparison with dexamethasone (DEX), and prednisolone acetate (PA).

Methods: After drug treatment of monkey TM cultures, MYOC protein in conditioned media (CM) was measured by Western blot and densitometry. MYOC mRNA levels were analyzed by qRT-PCR.

Comparison of the effect of multipurpose contact lens solutions on the viability of cultured corneal epithelial cells.

Purpose: To determine the effect of four marketed multipurpose contact lens solutions (MPSs) on corneal epithelial cell viability.

Methods: Comparison of the effect of MPS A (Renu MultiPlus, Bausch & Lomb), MPS B (OPTI-FREE Express, Alcon), MPS C (AQuify, CibaVision), and MPS D (OPTI-FREE RepleniSH, Alcon) on cell viability was performed by quantifying cellular ATP content, resazurin reduction, and lactate dehydrogenase (LDH) release in transformed human corneal epithelial cells (HCEpiC) and primary bovine corneal epithelial cells (BCEpiC).

Results: Significant reductions in cellular ATP content were observed at 40% solution and above with both MPS B and MPS D, compared to at 100% only for MPS A and MPS C, and similar results were obtained in BCEpiC.

Anti-inflammatory effects of besifloxacin, a novel fluoroquinolone, in primary human corneal epithelial cells.

Purpose: The aim of this study was to determine the anti-inflammatory effects of besifloxacin, a novel fluoroquinolone under clinical evaluation for the treatment of ophthalmic infections, in human corneal epithelial cells (HCEpiC).

Methods: Cytokine expression in primary HCEpiC was stimulated by interleukin-1beta (IL-1beta), and Luminex technology was used to determine the effect of besifloxacin on IL-1beta-induced cytokine release. Effect of besifloxacin on nuclear factor kappa B (NFkappaB), and mitogen-activated protein kinase (MAPK) was assessed by measuring inhibitory kappa B protein (IkappaB) degradation, NFkappaB nuclear translocation, and MAPK phosphorylation by Western blotting.

An epidermal growth factor (EGF) -dependent interaction between GIT1 and sorting nexin 6 promotes degradation of the EGF receptor.

G-protein coupled receptor (GPCR) kinase-2 interacting protein 1 (GIT1) is a multifunctional scaffolding protein that regulates epidermal growth factor receptor (EGFR) signaling pathways. We demonstrate that GIT1 interacts with sorting nexin 6 (SNX6), a member of the SNX family that increases EGFR trafficking between endosomes and lysosomes, thereby enhancing EGFR degradation. The GIT1-SNX6 interaction is increased 3-fold after treatment with EGF for 60 min.

GIT1 mediates HDAC5 activation by angiotensin II in vascular smooth muscle cells.

Objective: The G protein-coupled receptor (GPCR)-kinase2 interacting protein1 (GIT1) is a scaffold protein involved in angiotensin II (Ang II) signaling. Histone deacetylase-5 (HDAC5) has emerged as an important substrate of calcium/calmodulin-dependent protein kinase II (CamK II) in GPCR signaling. Here we investigated the hypothesis that Ang II-mediated vascular smooth muscle cell (VSMC) gene transcription involves GIT1-CamK II-dependent phosphorylation of HDAC5.

Gas6-axl receptor signaling is regulated by glucose in vascular smooth muscle cells.

Objective: The receptor tyrosine kinase Axl and its ligand Gas6 are involved in the development of renal diabetic disease. In vascular smooth muscle cells (VSMCs) Axl is activated by reactive oxygen species and stimulates migration and cell survival, suggesting a role for Axl in the vascular complications of diabetes.

Methods And Results: We investigated the effect of varying glucose concentration on Axl signaling in VSMCs.

Gas6 inhibits apoptosis in vascular smooth muscle: role of Axl kinase and Akt.

Axl is a receptor tyrosine kinase originally identified as a transforming gene product in human myeloid leukemia cells. Previously, we showed that Axl expression correlated with neointima formation in balloon-injured rat carotid, and that Axl expression was highly regulated by angiotensin II. In the present study we tested the mechanisms by which Axl regulates vascular smooth muscle cell (VSMC) growth focusing on its ability to inhibit apoptosis.