A phase III, placebo controlled clinical trial of 0.5% levofloxacin ophthalmic solution for the treatment of bacterial conjunctivitis.

AIM: To compare the efficacy and safety of levofloxacin 0.5% ophthalmic solution (Quixin) with placebo for treatment of bacterial conjunctivitis. METHODS: In this prospective, randomised, placebo controlled, double masked, multicentre study, 249 patients with bacterial conjunctivitis received either 0.5% levofloxacin (n = 126) or placebo (n = 123) for 5 days, administered every 2 hours on days 1-2, then every 4 hours on days 3-5. Cultures were obtained and signs/symptoms evaluated at baseline, interim, and final visits. The end point was the last evaluable observation. Primary microbial outcomes were based on culture results; clinical outcomes were based on resolution of cardinal signs. RESULTS: 117 patients (60 levofloxacin, 57 placebo) were evaluated. Microbial eradication rates were significantly greater with levofloxacin at all time points, reaching 90% at end point. In a subgroup analysis, differences in eradication rates at end point were most pronounced in children but were also statistically significant for levofloxacin in adults. Clinical cure rates were significantly greater with levofloxacin at final visit and end point. Statistically significant differences favouring levofloxacin were measured at end point for resolution of conjunctival discharge, bulbar conjunctival injection, palpebral conjunctival injection, burning/stinging, itching, and photophobia. Adverse events were similar between groups. Safety composite scores analysed by age indicated significantly fewer children on levofloxacin experienced worsening symptoms. CONCLUSIONS: Levofloxacin 0.5% ophthalmic solution is safe and effective for treatment of bacterial conjunctivitis.

Lens changes in hereditary hyperferritinemia-cataract syndrome.

PURPOSE: To provide detailed description and illustration of the lens changes found in hereditary hyperferritinemia-cataract syndrome, a newly reported autosomal dominant condition. METHODS: Observational case reports. A 19-year-old man was referred for evaluation of possible hereditary hyperferritinemia-cataract syndrome. His serum ferritin level was increased at 1291 microg/L during a routine screening examination. Genetic analysis revealed mutation G51C on chromosome 19, predicting an altered iron response element in L-ferritin mRNA. Subsequent evaluation of his 46-year-old father revealed similar findings. RESULTS: Multiple breadcrumb-like nuclear and cortical lens opacities were seen in this father-son pair. These cases represent the first detailed description and illustration of hereditary hyperferritinemia-cataract syndrome cataracts in the ophthalmic literature. CONCLUSION: Hereditary hyperferritinemia-cataract syndrome can be associated with distinct breadcrumb-like lens opacities. Recognition of these characteristic cataracts may aid identification and study of patients with this unusual disorder and provide insight into mechanisms of cataract formation.

Oral erythromycin treatment for childhood blepharokeratitis.

Blepharokeratitis is a chronic external ocular and adnexal inflammatory condition marked by erythematous and edematous lid margins, lid margin crusting and scaling, meibomian gland inflammation and inspissation, and conjunctival hyperemia. The associated keratitis usually involves the inferior cornea and is characterized by punctate epithelial keratopathy and marginal stromal infiltrates. The inflammation sometimes leads to corneal thinning, scarring, and vascularization. The standard therapy for adult blepharokeratitis includes lid hygiene, topical cortico-steroid preparations, and topical antibiotics. Oral tetracycline and its analogues, doxycycline and minocycline, are used in adults to treat associated meibomian gland dysfunction. Whereas blepharitis is common in children, blepharokeratitis is rare and is often associated with severe ocular and psychosocial morbidity. Treatment of youths may be problematic because of poor compliance with lid hygiene and therapy that includes drops and ointment.(1) Furthermore, the use of tetracycline and its analogues is contraindicated in children aged less than 8 years because it may cause dental enamel abnormalities. Isolated case reports have suggested that erythromycin may be a reasonable alternative to tetracycline in childhood blepharokeratitis.(2,3) We report on the successful treatment of this condition with oral erythromycin in 5 children.

Effect of eye rubbing on signs and symptoms of allergic conjunctivitis in cat-sensitive individuals.

OBJECTIVE: To evaluate the effect of eye rubbing on signs and symptoms of allergic conjunctivitis in cat-sensitive individuals. DESIGN: Two prospective, nonrandomized comparative studies. PARTICIPANTS: Thirteen patients in the first study and 20 patients in the second study with a documented history of acute allergic conjunctivitis induced by exposure to cats were enrolled. INTERVENTION: In the first trial, all patients had one eye rubbed 15 times by the investigator without exposure to airborne allergens. Both eyes were evaluated after 5, 15, 30, and 60 minutes using subject questionnaires and slit-lamp examination. At least 1 week later, each patient was exposed to cat dander for 75 minutes; 15 minutes after entering the cat room, each patient had one eye rubbed 15 times by the examiner. Subjects' eyes were then evaluated using questionnaires and slit-lamp examination. In the second trial, the visits were identical to the first trial, except that the rubbed eye in each visit was rubbed 20 times and with more force, and that patients wore masks during exposure to cat dander. MAIN OUTCOME MEASURES: In both studies, the difference between patients' rubbed and nonrubbed eyes with respect to ocular itching, chemosis, and hyperemia was noted 5, 15, 30, and 60 minutes after controlled eye rubbing. RESULTS: Without exposure to the cat room, rubbed eyes exhibited increased itching at 5 minutes in both studies and at 15 minutes in the second study (P < 0.05), increased chemosis at 5 and 15 minutes in the second study (P < 0.05), and increased hyperemia at 5 minutes in the second study (P < 0.05) compared with nonrubbed eyes. During exposure to cat dander, rubbed eyes consistently exhibited increased itching at 5, 15, and 30 minutes in the first and second study as well as at 60 minutes in the second study compared with nonrubbed eyes. Furthermore, during exposure to cat dander, rubbed eyes consistently exhibited increased chemosis at 5 and 15 minutes (P < 0.05) and increased hyperemia at 5, 15, and 30 minutes (P < 0.05) in the second study compared with nonrubbed eyes. CONCLUSIONS: Firm eye rubbing causes a mild and transient increase in ocular itching, chemosis, and hyperemia. However, after exposure to cat allergens in cat-sensitive individuals, the effects of eye rubbing are longer and more dramatic. Eye rubbing may play a role in ocular signs and symptoms of allergic conjunctivitis in cat-sensitive individuals, especially after exposure to cat dander.

Efficacy and safety of ketorolac tromethamine 0.5% and levocabastine 0.05%: a multicenter comparison in patients with seasonal allergic conjunctivitis.

This multicenter, double-masked, randomized, parallel-group study compared the efficacy and safety of ketorolac tromethamine 0.5% ophthalmic solution with levocabastine 0.05% and ketorolac tromethamine vehicle in patients with seasonal allergic conjunctivitis. One drop of ketorolac, levocabastine, or vehicle was instilled in each eye four times daily for 6 weeks. In the majority of efficacy variables, ketorolac produced the greatest improvements, followed by levocabastine and vehicle. Ketorolac was significantly more effective (P < .05) than vehicle in reducing mean itching scores, palpebral hyperemia, bulbar hyperemia, and edema. Patients treated with ketorolac reported significant improvements (P < .05) in their ability to sleep and to concentrate on work, compared with those who received vehicle. No significant differences were noted among the treatment groups in safety or tolerability. Ketorolac tromethamine 0.5% ophthalmic solution instilled four times daily is effective and safe in reducing the signs and symptoms of seasonal allergic conjunctivitis.

Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B.

We have studied mechanisms controlling activation of the gelatinase B gene (matrix metalloproteinase-9) by fibroblast growth factor-2 (FGF-2) during angiogenesis, and the effects of the natural product curcuminoids on this process. Using a transgenic mouse (line 3445) harboring a gelatinase B promoter/lacZ fusion gene, we demonstrate FGF-2 stimulation of reporter gene expression in endothelial cells of invading neocapillaries in the corneal micropocket assay. Using cultured corneal cells, we show that FGF-2 stimulates DNA binding activity of transcription factor AP-1 but not NF-kappaB and that AP-1 stimulation is inhibited by curcuminoids. We further show that induction of gelatinase B transcriptional promoter activity in response to FGF-2 is dependent on AP-1 but not NF-kappaB response elements and that promoter activity is also inhibited by curcuminoids. In rabbit corneas, the angiogenic response induced by implantation of an FGF-2 pellet is inhibited by the co-implantation of a curcuminoid pellet, and this correlates with inhibition of endogenous gelatinase B expression induced by FGF-2. Angiostatic efficacy in the cornea is also observed when curcuminoids are provided to mice in the diet. Our findings provide evidence that curcuminoids target the FGF-2 angiogenic signaling pathway and inhibit expression of gelatinase B in the angiogenic process.

Lepromatous uveitis diagnosed by iris biopsy.

Ocular leprosy is rarely seen in developed countries. We report the long-term follow-up of a patient with bilateral uveitis, glaucoma, and keratitis. Skin, iris and aqueous humor biopsies disclosed abundant Wade-Fite-positive organisms consistent with Mycobacterium leprae. Leprosy must be considered in the differential diagnosis of keratitis and uveitis.

A multicenter comparison of the ocular efficacy and safety of diclofenac 0.1% solution with that of ketorolac 0.5% solution in patients with acute seasonal allergic conjunctivitis.

Only one of several available ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) is currently FDA approved for use in acute seasonal allergic conjunctivitis (SAC). Sixty patients with SAC and moderate itching and bulbar conjunctival injection were enrolled in a multicenter, randomized, double-masked, parallel-group trial comparing diclofenac sodium (DS) with ketorolac tromethamine (KT). Patients instilled 1 drop four times daily while awake for 14 days. Ocular signs and symptoms were evaluated at one and two weeks. The primary efficacy variables were itching and bulbar conjunctival injection. For both treatments, the ocular allergy sign and symptom scores were comparable at baseline. Both treatments evaluated in this study were well tolerated. Significant clinical and statistical reductions from baseline were observed in the primary efficacy variables. Treatment group differences were observed for the pain/soreness score with an advantage observed for the DS group at 30 minutes and at day 7. Our conclusion is that diclofenac sodium and ketorolac tromethamine acted similarly to reduce the ocular signs and symptoms associated with acute seasonal allergic conjunctivitis. There was a statistically significant advantage for the DS group to be free of symptoms at the day 7 visit as compared to the KT group (20.7% vs. 3.2%).

Retinal safety of oral and topical ofloxacin in rabbits.

Ofloxacin is a broad spectrum fluoroquinolone antibiotic with good ocular penetration. We investigated the potential for retinal toxicity associated with increased intraocular penetration following intensive topical, oral, and combined topical and oral administration. We confirmed ofloxacin concentrations in aqueous and vitreous following these forms of administration. Rabbits received either topical, oral, or a combination of oral and topical ofloxacin. Topical administration consisted of one drop of ofloxacin 0.3% drops given every thirty minutes for a total of eight doses. Oral ofloxacin was administered at a dose of 10 mg (4 mg/kg for average weight 2.5 kg rabbit) every 12 hours for a total of three doses. Six rabbits were followed longitudinally for 4 weeks for evidence of retinal toxicity by indirect ophthalmoscopy and serial ERGs. Electron and light microscopic histopathologic examination of the retina were performed 4 weeks following drug administration. To verify intraocular penetration, ten rabbits received identical dosing schedules followed by HPLC measurement of aqueous and vitreous drug concentrations at 1, 4, 8, 12, and 24 hours following dose completion. No evidence of retinal toxicity was detected by indirect ophthalmoscopy, electroretinography, or histopathological examination. Vitreous ofloxacin levels were highest after combined oral and topical administration, peaking at 0.892 microgram/ml 8 hours following dosage completion. The peak vitreous level following oral administration was 0.230 microgram/ml and 0.026 microgram/ml following topical administration. Peak aqueous humor levels were achieved one hour following drug administration and were 11.400 micrograms/ml after topical, 0.206 microgram/ml after oral, and 8.180 micrograms/ml after combined administration. Our study suggests that intensive topical and oral ofloxacin administration does not cause retinal toxicity in rabbits, despite achieving effective aqueous and vitreous humor antimicrobial concentrations.

Role of matrix metalloproteinases in failure to re-epithelialize after corneal injury.

Delayed re-epithelialization of the cornea after injury usually precedes stromal ulceration. Previous findings using a rat thermal injury model suggested that re-epithelialization is impeded by products of resident corneal cells, which destroy adhesive structures at the basement membrane zone. In this study, we provide additional evidence for this concept. Failure to re-epithelialize was found to correlate with an increase in the amounts of gelatinolytic matrix metalloproteinases present in the rat cornea. One of these gelatinases, gelatinase B, is synthesized by the resident corneal cells, and inhibitions of its synthesis correlated with inhibition of basement membrane dissolution. The matrix metalloproteinases collagenase and stromelysin are also synthesized by resident corneal cells in thermally injured corneas of rabbits, but the timing of bulk enzyme synthesis correlated more closely with deposition of repair tissue in the stroma than with failure to re-epithelialize. Nevertheless, in human corneas with repair defects, gelatinase B and collagenase are synthesized by cells in the basal layer of the epithelium directly adjacent to the basement membrane, suggesting that both could participate in dissolution of this structure. Importantly, treatment of thermally injured corneas with a synthetic inhibitor of matrix metalloproteinases significantly improved basement membrane integrity. These data support the concept that over-expression of matrix metalloproteinases by resident corneal cells impedes re-epithelialization after some types of corneal injury.

Efficacy and safety of rimexolone 1% ophthalmic suspension vs 1% prednisolone acetate in the treatment of uveitis.

PURPOSE: Two multicenter studies compared the efficacy and safety of rimexolone 1% ophthalmic suspension (Vexol 1%, Alcon) and 1% prednisolone acetate (Pred Forte, Allergan). METHODS: Patients with acute uveitis, recurrent iridocyclitis, or chronic uveitis treatable by topical corticosteroid were enrolled. Treatment regimen was one or two drops every hour during Week 1, every two hours during Week 2, four times a day during Week 3, and once a day for the last three days. Efficacy and safety were determined on Days 3, 4, 7 to 10, 14, 21, and 28. A poststudy evaluation was conducted 36 to 72 hours after treatment was stopped. RESULTS: When anterior chamber cell and flare were measured, rimexolone 1% was found to be as effective as 1% prednisolone. The largest difference observed between treatments was 0.5 score unit, not clinically significant. There were no statistically significant differences in cell scores in either study (P > .05). No statistically significant differences in flare scores were found except at Day 28 in Study One (P = .04). Also, prednisolone was found to be more likely than rimexolone to cause a clinically significant increase (10 mm Hg or more) in intraocular pressure (1.7 times more likely in Study One, eight times more likely in Study Two). CONCLUSION: Rimexolone 1% ophthalmic suspension is safe and effective for the treatment of uveitis.

Pathogenesis of corneal infection: binding of Pseudomonas aeruginosa to specific phospholipids.

Clinical isolates of Pseudomonas aeruginosa were examined for binding interactions with phospholipids of corneal epithelium. Thin-layer chromatography (TLC) of lipids extracted from corneal epithelia followed by staining with an ammonium molybdate spray reagent revealed three phospholipid components, PL1, PL2, and PL3. The chromatographic mobility of PL1 was similar to that of the phospholipid standards phosphatidylinositol (PI) and phosphatidylserine (PS), which were not well resolved from one other; PL2 and PL3 comigrated with the standards phosphatidylcholine and phosphatidylethanolamine, respectively. By use of a TLC-bacterial overlay procedure, 35S-labeled P. aeruginosa organisms were shown to bind to PL1 but not to PL2 or PL3. P. aeruginosa binding to PL1 was concentration dependent. Alkaline methanolysis abolished the binding. PL1 was separated into two components, PL1-I and PL1-S, by chromatography on borate-treated TLC plates. Both PL1-I and PL1-S contained binding sites for P. aeruginosa. Mass spectral analysis identified PL1-I and PL1-S as PI and PS, respectively. Radiolabeled P. aeruginosa organisms were subsequently shown to bind to commercially available bovine PI and PS and synthetic dipalmitoyl-PS but not to other phospholipid standards, including bovine SM and PC or synthetic dioleoyl- and distearoyl-PC. A control Escherichia coli strain did not bind to either PS or PI. Tetramethylurea, a disrupter of hydrophobic associations, did not influence the binding of P. aeruginosa to PS or PI. P. aeruginosa bound to the monolayers of corneal epithelial cells. P. aeruginosa binding to the monolayer cultures as well as to rabbit corneas pretreated with exogenous PS and PI was significantly higher than that to those preincubated with PC or medium alone. The data suggest that phospholipids PS and PI present in mucus or on the cell surface may function as P. aeruginosa receptors and contribute to selective bacterium-host interactions responsible for initial colonization.

In vivo evaluation of a collagen corneal allograft derived from rabbit dermis.

BACKGROUND: This study evaluates epithelialization, clarity, intraocular inflammation, and fibroblast ingrowth of a collagen corneal allograft derived from rabbit dermis. METHODS: Dermal collagen fibers were dispersed intact and chemically modified to make them soluble. The allografts consisted of a fibrous, opaque peripheral zone and a central clear area. Twelve New Zealand white rabbits underwent penetrating keratoplasty with implantation of an allograft. The grafts were evaluated daily for clarify, anterior segment inflammation, and extent of reepithelialization with a slit-lamp microscope. RESULTS: Epithelialization of the fibrous peripheral zone of the graft ranged from 0% to 90%. The central clear area did not epithelialize in any of the animals. Fibroblasts migrated into the peripheral zone in all eyes. Complications included ulceration of the central clear area in two eyes. There was no ulceration or leakage at the graft-host interface and no synechia, fibrous, or inflammatory retrocorneal membranes in any of the eyes. CONCLUSIONS: Our study is the first to describe the method of modifying dermal type I collagen into a clear corneal allograft. Survival of the corneal collagen allograft beyond 1 month may be limited by several factors including lack of epithelialization of the central clear area.

The effect of trephination on corneal topography.

BACKGROUND AND OBJECTIVE: A prospective study was performed to assess the effect of trephination on corneal curvature. MATERIALS AND METHODS: Thirty-seven fresh porcine globes with intact corneal epithelium were used. Radius of curvature, central dioptric power, and powers and axes of the steepest and flattest meridians were obtained using a vertically mounted computerized videokeratography unit. Following 8-mm vacuum trephination of the central donor corneas, the said parameters were reassessed on the resultant buttons. No globes with epithelial defects were included in the study. RESULTS: The mean corneal radius of curvature (mm) increased from 8.68 +/- 0.79 to 10.46 +/- 3.24 (P = .005), the central dioptric power (D) decreased from 39.36 +/- 3.84 to 36.31 +/- 10.15 (P = .08), and the total corneal asphericity (D) increased from 5.03 +/- 2.99 to 7.47 +/- 3.42 (P = .0001). No significant changes in the axes of the steepest and the flattest meridians were noted following trephination. CONCLUSION: Trephination leads to significant corneal flattening and increased asphericity. Corneal topography can be used successfully as a research tool for whole globes and trephined buttons.

Plasma membrane sialoglycoproteins of human corneal epithelium in culture.

A number of studies, using either rat or rabbit models, have focused on delineating the role of cell surface glycoconjugates in corneal epithelial cell migration and wound healing. We have recently identified the cell surface sialoglycoproteins of rabbit corneal epithelium and have shown that the levels of at least three membrane glycoproteins are markedly altered during cell migration. Because species-related differences may be present, it is important to select an appropriate animal model for studies designed to contribute to the understanding of the mechanism of human corneal wound healing. The purpose of this study was to identify the cell surface sialoglycoproteins of human corneal epithelium. Plasma membrane sialoglycoproteins of primary cultures of human corneal epithelium were labeled with NaB3H4 after oxidation by mild NaIO4 treatment. The labeled glycoproteins were analyzed by SDS-polyacrylamide gel electrophoresis and fluorography. Four different preparations of human corneal epithelial cell cultures were analyzed, and results were compared with those of rabbit corneal epithelium. Of the 11 radiolabeled sialoglycoproteins we identified recently in rabbit corneal epithelium, eight were also present in human corneal epithelium. These similarities in the electrophoretic patterns of the plasma membrane glycoproteins of the two species suggest that rabbit is most likely an appropriate animal model for studies designed to contribute to the understanding of the structure and function of cell surface glycoproteins of human corneal epithelium.

Results of a survey of patients with ocular allergy treated with topical ketorolac tromethamine.

Exposure of the eye to airborne particles in patients predisposed to allergy often results in the signs and symptoms of allergic conjunctivitis such as red, itchy eyes and ocular discharge. The mediators of these allergic symptoms include histamine, inflammatory substances such as prostaglandins, and other products of arachidonic acid metabolism (ie, leukotrienes). Ketorolac tromethamine is a nonsteroidal anti-inflammatory agent that inhibits the activity of cyclooxygenase, one of the two major enzymes responsible for the conversion of arachidonic acid to inflammatory substances. A multicenter patient survey was performed to evaluate the effectiveness of topical ketorolac tromethamine in treating the symptoms of allergic conjunctivitis. After ocular administration of ketorolac tromethamine, 90% (246/272) of patients reported that their eyes felt better. Eighty-four percent (173/206) of respondents rated ketorolac tromethamine as good to excellent in relieving their overall symptoms of ocular allergy, and 86% (217/251) of patients found the study drug produced good to excellent relief of their ocular itching usually within minutes to 1 hour of administration. Results of this survey found ketorolac tromethamine is effective in relieving ocular itching, the hallmark symptom of allergic conjunctivitis. In addition, these results provide further evidence that the products of arachidonic acid metabolism contribute to the symptoms of allergic conjunctivitis.