Efficacy, Drug Sensitivity, and Safety of a Chronic Ocular Hypertension Rat Model Established Using a Single Intracameral Injection of Hydrogel into the Anterior Chamber.

BACKGROUND Chronic ocular hypertension (COH) models mostly focus on changes in intraocular pressure (IOP) and loss of retinal ganglion cells (RGCs). The present study evaluated important glaucoma-related changes in visual function, response to common ocular hypotensive drugs, and safety for our previously developed rat model. MATERIAL AND METHODS The model was established through a single injection of hydrogel into the anterior chambers. Efficacy was assessed through F-VEP by measuring latency and amplitude of P1. We evenly divided 112 rats into 4 groups: control and COH at 2, 4, and 8 weeks. Response to 5 common drugs (brimonidine, timolol, benzamide, pilocarpine, and bimatoprost) were each tested on 6 rats and assessed using difference in IOP. Safety assessment was conducted through histological analysis of 24 rats evenly divided into 4 groups of control and COH at 2, 4, and 8 weeks. Corneal endothelial cells (CECs) of 24 additional rats were used to determine toxic effects through TUNEL and CCK-8 assays. RESULTS P1 latency and amplitude of VEP demonstrated the model is effective in inducing optic nerve function impairment. Only the drug pilocarpine failed to have an obvious hypotensive effect, while the other 4 were effective. CECs at 2, 4, and 8 weeks showed no significant differences from control groups in results of histological analysis, TUNEL, and CCK-8 assays. CONCLUSIONS A single injection of hydrogel into the anterior chamber is effective for modeling COH, can respond to most commonly used hypotensive drugs, and is non-toxic to the eyes.

Development of a Novel Intraocular-Pressure-Lowering Therapy Targeting ATX.

Elevated intraocular pressure (IOP) is the major cause of glaucoma, which is the second leading cause of blindness. However, current glaucoma treatments cannot completely regulate IOP and progression of glaucoma. Our group recently found that autotaxin (ATX) activity in human aqueous humor (AH) was positively correlated with increased IOP in various subtypes of glaucoma. To develop new IOP-lowering treatments, we generated a novel ATX inhibitor as an ophthalmic drug by high-throughput screening, followed by inhibitor optimization. Administration of the optimized ATX inhibitor (Aiprenon) reduced IOP in laser-treated mice exhibiting elevated IOP and higher level of ATX activity in AH and normal mice in vivo. The stimulation of ATX induced outflow resistance in the trabecular pathway; however, administration of Aiprenon recovered the outflow resistance in vitro. The in vitro experiments implied that the IOP-lowering effect of Aiprenon could be correlated with the altered cellular behavior of trabecular meshwork (TM) and Schlemm's canal endothelial (SC) cells. Overall, our findings showed that ATX had major impact in regulating IOP as a target molecule, and potent ATX inhibitors such as Aiprenon could be a promising therapeutic approach for lowering IOP.

Effect of glucosamine on intraocular pressure: a randomized clinical trial.

PurposeThe purpose of the study was to investigate ocular hypertensive effect of exogenous glucosamine in comparison with placebo in patients with osteoarthritis.Patients and methodsIn this double-masked randomized clinical trial, 88 patients with osteoarthritis were included. Forty-four patients were randomized into either glucosamine sulfate or the placebo group.Comprehensive ophthalmologic exam including intraocular pressure (IOP) at baseline, month 1, and 3 was performed. Ocular response analyzer parameters were also checked at baseline and month 3.ResultsThe mean IOP at the time of presentation was 12.4±2.7 mm Hg in glucosamine and 13±2.8 mm Hg in the placebo group (P=0.329). At month 1 the corresponding values were 12.6±2.4 and 12.9±2.4 mm Hg (P=0.868), and at 3 months follow-up were 13.5±2.3 and 13±2.7 mm Hg (P=0.002), respectively. About 34.1% in treatment and 12.5% in the placebo group had clinically significant (defined as ≥ 2 mm Hg) rise in IOP at final follow-up (P=0.023). Mean age in those with significant rise in IOP was 66 vs 57.7 years in patients with <2 mm Hg (P=0.034). The ORA parameters remained unchanged in both the groups during the course of study.ConclusionGlucosamine supplement therapy causes statistically significant rise of IOP, which is more pronounced in elderly patients. Clinical implication of this finding needs further evaluation.

Orbital inflammation secondary to a delayed hypersensitivity reaction to sub-Tenon's hyaluronidase.

We report a rare case of a delayed orbital inflammation with raised intraocular pressure as a result of hyluronidase allergy following sub-Tenon's anaesthesia. Here, we have shown evidence to prove the orbital inflammation to be an allergic response to hyluronidase with a skin patch test. This is the first case to our knowledge of a delayed hypersensitivity reaction to sub-Tenon's hyluronidase comprising of an initial exposure to hyluronidase in the fellow eye with no subsequent allergic response, but with a subsequent delayed reaction to hyluronidase during a second eye cataract surgery. This case demonstrates hyaluronidase allergy should be considered as a differential diagnosis among patients presenting with acute post-operative orbital inflammation, even if there is a history of previous exposure to hyaluronidase in the fellow eye with no subsequent allergic response.

Microbead-induced ocular hypertensive mouse model for screening and testing of aqueous production suppressants for glaucoma.

PURPOSE: To characterize the microbead-induced ocular hypertension (OHT) mouse model and investigate its potential use for preclinical screening and evaluation of ocular hypotensive agents, we tested the model's responses to major antiglaucoma drugs. METHODS: Adult C57BL/6J mice were induced to develop OHT unilaterally by intracameral injection of microbeads. The effects of the most commonly used ocular hypotensive drugs, including timolol, brimonidine, brinzolamide, pilocarpine, and latanoprost, on IOP and glaucomatous neural damage were evaluated. Degeneration of retinal ganglion cells (RGCs) and optic nerve axons were quantitatively assessed using immunofluorescence labeling and histochemistry. Thickness of the ganglion cell complex (GCC) was also assessed with spectral-domain optical coherence tomography (SD-OCT). RESULTS: A microbead-induced OHT model promptly responded to drugs, such as timolol, brimonidine, and brinzolamide, that lower IOP through suppressing aqueous humor production and showed improved RGC and axon survival as compared to vehicle controls. Accordingly, SD-OCT detected significantly less reduction of GCC thickness in mice treated with all three aqueous production suppressants as compared to the vehicle contol-treated group. In contrast, drugs that increase aqueous outflow, such as pilocarpine and latanoprost, failed to decrease IOP in the microbead-induced OHT mice. CONCLUSIONS: Microbead-induced OHT mice carry dysfunctional aqueous outflow facility and therefore offer a unique model that allows selective screening of aqueous production suppressant antiglaucoma drugs or for studying the mechanisms regulating aqueous humor production. Our data set the stage for using GCC thickness assessed by SD-OCT as an imaging biomarker for noninvasive tracking of neuronal benefits of glaucoma therapy in this model.

Activity of crude cold-water extract of the culinary-medicinal oyster mushroom, Pleurotus ostreatus (Jacq.:Fr.) P.Kumm. (higher Basidiomycetes), and timolol maleate on induced ocular hypertension.

Aqueous crude cold-water extract from the fruiting body of the culinary-medicinal oyster mushroom Pleurotus ostreatus was assessed for activity against increased intra-ocular pressure (IOP) in mice. A 0.1% dexamethasone instillation was used to raise the intra-ocular pressure in the animals above the 21-mmHg threshold limit. The extract has intrinsic anti-hypertensive properties that are dose dependent. A comparison analysis indicated that 150 mg/mL of the crude extract produced 57.69% reduction in the intra-ocular pressure, while doses of 100 mg/ mL and 200 mg/mL produced 44.78% and 70.03% IOP reduction, respectively, compared with timolol maleate with 57.69%. The results were significant at 0.05 confidence limit (p < 0.05) when compared to a placebo and therefore support its use for the treatment of increased intra-ocular pressure.

Retinal oxidative stress induced by intraocular hypertension in rats may be ameliorated by brimonidine treatment and N-acetyl cysteine supplementation.

PURPOSE: To investigate the effect of brimonidine and N-acetyl cysteine (NAC) on retinal oxidative status under ocular hypertension. MATERIALS AND METHODS: Ocular hypertension is produced in right eyes of 60 rats through intraocular injection of sodium hyaluronate. The left eyes received intracameral saline as sham. Twenty right eyes (brimonidine group) received topical brimonidine twice a day for a week. Other 20 eyes received intraperitoneal NAC (NAC group) once a day. Another group of 20 eyes were followed without any drugs but only intracameral sodium hyaluronate (sodium hyaluronate group) into right eyes. RESULTS: Intraocular injection of sodium hyaluronate increased intraocular pressure for a week and caused retinal peroxidation and decreased glutathione peroxidase and catalase levels. Brimonidine and NAC treatment reversed the retinal oxidative stress created by high intraocular pressure. CONCLUSIONS: Brimonidine and NAC supplementation provide antioxidative properties to retina and decrease retinal damage induced by ocular hypertension.

A water-soluble carbon monoxide-releasing molecule (CORM-3) lowers intraocular pressure in rabbits.

BACKGROUND: Carbon monoxide-releasing molecules (CORMs) are a novel group of substances that are capable of modulating physiological functions via the liberation of CO. AIMS: This study was undertaken to investigate the effects of CORM-3, a water-soluble CO-releasing agent, on two rabbit models of ocular hypertension. METHODS: Ocular hypertension was induced by injecting alpha-chymotrypsin in the rabbit eye. The dose-response effect of CORM-3 on IOP was assessed by topical administration of the drug (0.001, 0.01, 0.1 and 1%). Ocular hypertension was also obtained by weekly subconjunctival injection of betamethasone, and animals were treated topically with CORM-3. A group of animals in both models was treated with the inactive form of the drug (iCORM-3). RESULTS: CORM-3 induced a dose-dependent reduction in IOP in rabbits treated with alpha-chymotrypsin. A similar reduction in IOP was observed in rabbits with betamethasone-induced ocular hypertension treated with the drug. Treatment with the iCORM-3 had no effect on IOP in both models. CONCLUSIONS: Treatment with CORM-3 is associated with a reduction in IOP in two different rabbit models of ocular hypertension. These results support previous findings on the effect of haem oxygenase-derived CO on IOP and suggest a direct involvement of CO system in the regulation of ocular pressure probably through the modulation of aqueous humour dynamics.

Effect of topical Ginkgo biloba extract on steroid-induced changes in the trabecular meshwork and intraocular pressure.

OBJECTIVE: To study the effects of Ginkgo biloba extract (GBE) on dexamethasone (DEX)-induced ocular hypertension. METHODS: Rabbits aged 7 weeks received topical TobraDEX (Alcon Labs, Hünenberg, Switzerland) and/or 5 microg of GBE four times daily for 14 days. Intraocular pressure (IOP) was recorded every 3 days. After enucleation, trabecular meshwork (TM) cellularity and extracellular matrix deposition were graded. The effect of GBE on apoptosis and expression of myocilin and cell stress-related genes in DEX-treated human TM cells were studied by immunofluorescence, Western blotting, and quantitative polymerase chain reaction. RESULTS: Ginkgo biloba extract suppressed DEX-induced IOP elevation in rabbits. It reduced the DEX-associated accumulation of extracellular materials within the cribriform layers of the TM and achieved better TM cellularity. In cultured human TM cells, GBE substantially attenuated anti-Fas ligand-induced apoptosis and reduced DEX-induced myocilin expression. Ginkgo biloba extract modulated the expression of alphaB-crystallin and heat-shock proteins 70 and 90alpha but not other stress-related genes. Furthermore, changes associated with DEX were found less in GBE-treated or GBE-primed TM cells. CONCLUSION: We showed that GBE, a nontoxic, antiapoptotic, herbal compound significantly suppressed steroid-induced IOP elevation in rabbits and it seems to prevent the adverse effects of DEX on TM cells. CLINICAL RELEVANCE: Ginkgo biloba extract could be a therapeutic agent or dietary supplement to prevent steroid-induced ocular hypertension.

Oculohypotensive effects of foeniculum vulgare in experimental models of glaucoma.

PURPOSE: Evaluation of oculohypotensive activity of single drop application of aqueous extract of Foeniculum vulgare in experimental models of glaucoma. METHODS: The evaluation of oculohypotensive activity of Foeniculum vulgare was done in rabbits with normal intraocular pressure (IOP) and with experimentally elevated IOP. The experimental increase in IOP was achieved using water loading and steroid induced glaucoma models. RESULTS: The aqueous seed extract of Foeniculum vulgare exhibited 17.49, 21.16 and 22.03% reduction of intraocular pressure (IOP) in normotensive rabbits at 0.3%, 0.6% and 1.2% (w/v) concentrations respectively. The 0.6% concentration was further evaluated in acute and chronic models of glaucoma. A maximum mean difference of 31.20% was observed between vehicle treated and extract treated eyes in water loading model while a maximum mean IOP lowering of 31.29% was observed in steroid induced model of glaucoma. CONCLUSIONS: The aqueous extract of Foeniculum vulgare possesses significant oculohypotensive activity, which was found to be comparable to that of timolol. Further investigations into the mechanism of action, possible toxicity and human clinical trials are warranted before the Foeniculum vulgare finds place in the arsenal of antiglaucoma drugs prescribed by physicians.

Change in intraocular pressure within 1 week of phacoemulsification and intraocular lens implantation using Adatocel.

PURPOSE: To examine the change in intraocular pressure (IOP) within 1 week of phacoemulsification and foldable posterior chamber intraocular lens (PC IOL) implantation using Adatocel (hydroxypropyl methylcellulose 2% [HPMC]). SETTING: Department of Ophthalmology, University of Sciences, Faculty of Medicine, Pécs, Hungary. METHODS: In this prospective study, the IOP in 118 eyes of 118 patients (57 men, 61 women, mean age 68 years +/- 7.8 [SD]) with no history of glaucoma was assessed by Goldmann applanation tonometry 2 to 3, 6 to 8, and 22 to 24 hours and 1 week after uneventful phacoemulsification and PC IOL implantation. The effect of the removal of Adatocel ("partial removal" from the anterior chamber [AC] only versus "complete removal" from behind of the IOL as well), the lens type (Medicontur 601 HP versus Bausch & Lomb Hydroview), and the type of anesthesia (topical versus parabulbar) were compared. Statistical analysis was performed using the Student t test, and P< or =.05 was considered statistically significant. RESULTS: The mean preoperative IOP was 13.83 +/- 2.5 mmHg. There were no significant differences at any time in postoperative IOP measurements between the 2 IOL types and the 2 modes of anesthesia. At 2 to 3 hours, 6 to 8 hours, and 22 to 24 hours, the IOP was significantly higher in the 30 eyes in which the Adatocel was partially removed (from the AC only) than in the 88 eyes in which it was completely removed (from behind the PC IOL as well) (P< or =.05, P< or =.01, and P< or =.001, respectively). CONCLUSION: Severe postoperative IOP spikes in nonglaucomatous patients after uneventful phacoemulsification cataract surgery are rare. The type of implanted PC IOL and the mode of anesthesia had no significant effect on postoperative IOP. Total removal of the ophthalmic viscosurgical device, even when using HPMCs such as Adatocel, is necessary to prevent postoperative IOP spikes.

[Problems of perioperative period in patients with Steinert's myotonic dystrophy operated due to cataract]. / problemy okresu okolooperacyjnego u chorych na dystrofie miotoniczna steinerta, operowanych z powodu zacmy.

Steinert's myotonic dystrophy is a genetically conditioned systemic disease with symptoms related to circulatory, respiratory, muscular, endocrine and mental disturbances. Most if not all of these patients develop lens opacification as a presenting symptom and need to undergo cataract surgery. Nevertheless, selection of a type of anaesthesia can arise to a problem in these patients because local anaesthesia can be insufficient whereas general endotracheal anaesthesia is known, to potentially provoke serious postoperative complications. In this contribution we discuss problems we faced during cataract surgery in three siblings affected by Steinert's myotonic dystrophy. Two of them were operated on in local anaesthesia and developed intraoperative problems related to sudden increase of intraocular pressure, bleeding and vitreous efflux. After receiving a thorough examination the youngest of the three was operated on under short acting general intravenous anaesthesia (propofol and/or benzodiazepines, piperidine derived opioids, non-polarizing paralytics). We conclude that short acting general intravenous anaesthesia can help in avoiding both, local ocular complications during surgery and problems in the postoperative period.

AL-2512, a novel corticosteroid: preclinical assessment of anti-inflammatory and ocular hypertensive effects.

The anti-inflammatory efficacy and ocular hypertensive effect of AL-2512 were characterized in rodent and feline models of ocular inflammation. Neutrophil influx into ocular tissue following topical ocular administration of test drugs was evaluated in models of endotoxin-induced uveitis. In rats, the anti-inflammatory efficacy of AL-2512 was compared with that of 0.1% dexamethasone. Test drug or vehicle was administered topically before subplantar injection of endotoxin. Neutrophil influx was assessed at 24 hours. Feline eyes, injected intravitreally with endotoxin, were treated topically with 0.1% AL-2512, 1.0% prednisolone acetate or vehicle at various timepoints before and after endotoxin injection. At 12 hours, protein concentration and leukocyte count in aqueous humor were determined. In the feline intraocular pressure (IOP) model, after baseline IOP values were established, AL-2512, dexamethasone, or vehicle was administered topically to both eyes of cats. IOP was measured daily before and during treatment. Topical ocular administration of AL-2512 inhibited endotoxin-induced leukocyte influx in rodent and feline models of uveitis. In rats, AL-2512 significantly inhibited neutrophil influx by 89%, compared with 93% by dexamethasone. In feline eyes, AL-2512 significantly (p < 0.05) inhibited leukocyte infiltration of aqueous humor by 59%, compared to 37% inhibition by prednisolone acetate. Intraocular pressure in cats treated for 32 days with AL-2512 or dexamethasone increased 6% and 18%, respectively. The ocular anti-inflammatory effect of AL-2512 was equivalent to dexamethasone and superior to prednisolone acetate in rat and feline models of ocular inflammation, respectively. This steroid provides anti-inflammatory efficacy equivalent to dexamethasone with a reduced risk of inducing ocular hypertension.

Elevated intraocular pressure associated with steroid treatment for infantile spasms.

PURPOSE: To evaluate the ocular changes and medical and surgical therapy after high-dose systemic steroid treatment in babies with infantile spasm and hypsarrhythmia. DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS: In 5 of the 9 (55%) babies with infantile spasm exposed to systemic corticosteroid treatment, an increase in intraocular pressure (IOP) and optic disc cupping was observed. INTERVENTION: Ophthalmic examination under mild sedation was conducted 3 to 4 weeks after initiation of systemic therapy. Antiglaucoma treatment was given to the patients found to have high IOPs and cup-to-disc ratio changes. Routine follow-up was continued until systemic therapy was completed. MAIN OUTCOME MEASURES: Controlled IOP with a decrease in cupping damage after antiglaucoma therapy. RESULTS: Five patients required antiglaucoma treatment; one also underwent augmented trabeculectomy. Mean IOP decreased in this subgroup from 30.1 +/- 9.5 mmHg to 15.4 +/- 4.2 mmHg in the right eye (P = 0.043) and from 32.6 +/- 7.4 mmHg to 15.2 +/- 1.8 mmHg in the left eye (P = 0.043). Mean cup-to-disc ratio improved from 0.53 +/- 0.2 to 0.37 +/- 0.04 in the right eye (P = 0.06) and from 0.57 +/- 0.12 to 0.35 +/- 0.05 in the left eye (P = 0.042). CONCLUSIONS: The rapid onset of IOP and cup-to-disc ratio changes in patients with infantile spasm and hypsarrhythmia treated by high-dose corticosteroids necessitates early and intensive monitoring to prevent anatomic ocular damage and visual impairment in the future.

Retinal and choroidal vascular occlusion after posterior sub-tenon triamcinolone injection.

PURPOSE: To report a case of retinal and choroidal vascular occlusion occurring as a complication after posterior sub-Tenon triamcinolone injection for treatment of uveitic cystoid macular edema. DESIGN: Interventional case report. METHODS: Retrospective study. A 32-year-old woman with uveitis and cystoid macular edema underwent a right posterior sub-Tenon injection of triamcinolone (40 mg/ml, 1 ml total) through a superotemporal approach after topical anesthesia. After the procedure, the patient experienced severe eye pain, orbital ecchymosis, and globe proptosis consistent with retrobulbar hemorrhage. RESULTS: Dilated fundus examination of the right eye (OD) demonstrated multiple intraretinal hemorrhages with particulate white emboli occluding the retinal and choroidal vessels. Visual acuity was no light perception. Ocular massage and hypotensive therapy was initiated for an intraocular pressure of 50 mm Hg. Canthotomy and cantholysis were performed. A total of 39 months post-incident, her visual acuity improved to 20/100. CONCLUSION: Posterior sub-Tenon triamcinolone injection can rarely result in retinal and choroidal occlusion. Immediate intervention may preserve limited visual acuity.

[Intraocular pressure after phacoemulsification and implantation of silicone plate haptic intraocular lenses without viscoelastics]. / Intraokulardruck nach Phakoemulsifikation mit Implantation einer Silicon-Plattenhaptik-Intraokularlinse ohne Viskoelastika.

BACKGROUND: A rise in intraocular pressure (IOP) after cataract operation is a well known problem. Avoidance of the use of viscoelastics seems to solve the problem. PATIENTS AND METHODS: The IOP was measured in a group of 33 eyes of 33 patients one day before, as well as 6 hours, 24 hours, and 7 days after phacoemulsification and implantation of a foldable silicone plate haptic intraocular lens without viscoelastics and by means of an injector and of the anterior chamber maintainer. RESULTS: Mean preoperative IOP was 16.1 +/- 3.9 mm Hg (range 10 to 28 mm Hg). Postoperatively mean IOP was 12.3 +/- 3.3 mm Hg (range 5 to 18 mm Hg) after 6 hours (p < 0.0001), 13.8 +/- 2.8 mm Hg (range 7 to 19 mm Hg) after 24 hours (p = 0.032), and 15.5 +/- 3.4 (range 10 to 24) after one week (p = 0.39). In none of the eyes was the pressure in the first 24 hours higher than 18 mm Hg. When excluding the 4 patients with glaucoma and PEX or when taking them as a separate group, the results were similar. CONCLUSIONS: Pressure elevation after cataract operation without the use of viscoelastic substances can be avoided, thus contributing not only to lower costs but also to a higher safety.

Pharmacological profile of a new topical pilocarpine formulation.

A new formulation based on pilocarpine hyaluronate salt has been shown to improve the bioavailability of the drug and to extend the duration of activity. We evaluated the extent of intraocular pressure reduction, the duration of action and the kinetics of miotic response of this formulation in comparison with a commercial preparation with the same drug concentration. Ocular hypertension in the rabbit was induced by alpha-chymotrypsin or by water loading. The hypotensive effect of the new formulation treatment was significantly greater and longer than that observed in rabbit eyes treated with the commercial preparation both in the normotensive and in the hypertensive animals. Furthermore, we evaluated the miotic response in normotensive rabbits showing a greater miotic response and an extended duration when the eyes were treated with the new formulation. The pharmacological profile of the new formulation described in this study indicates an increase of efficacy and duration of action compared to the commercial preparation.