Naoko Shibata

Safety comparison of additives in antiglaucoma prostaglandin (PG) analog ophthalmic formulations

Purpose To investigate the safety of five types of antiglaucoma prostaglandin analog ophthalmic formulations, and to clarify their differences in accordance with contained additives (preservatives and surface-active agents). Methods The following five types of ophthalmic solutions and three types of additives were investigated: latanoprost (Xalatan®; latanoprost), tafluprost (Tapros®; tafluprost), bimatoprost (Lumigan®; bimatoprost), travoprost (Travatan®; travoprost), travoprost (Travatan Z®; travoprost-Z), benzalkonium chloride (BAK), polyoxyethylene hardening castor oil 40 (HCO-40), and polysorbate 80 (P-80). These experimental solutions were exposed to the cultured cells of a rabbit-derived corneal cell line for a certain time, and the exposure time causing 50% cell damage (CD50), indicated by the ratio of viable cells to total cells was calculated (in vitro). In addition, corneal resistance (CR) was measured and CR ratio (post-treatment CR/pretreatment CR × 100) was calculated (in vivo). Results CD50 of each ophthalmic solution was the longest with tafluprost, followed by travoprost-Z, bimatoprost, travoprost, and latanoprost. CD50 of 0.005%, 0.01%, and 0.02% BAK was 14.5 minutes, 8.1 minutes, and 4.0 minutes, respectively. The number of viable cells decreased to 60%, 8 minutes after exposure with HCO-40, and 30 minutes after being exposed to P-80. The CR ratio was 81.0% with travoprost and 82.0% with latanoprost, indicating a significant posttreatment reduction of CR (P < 0.05). The CR ratio did not decrease after treatment with tafluprost, travoprost-Z, or bimatoprost. The CR ratio of 0.005%, 0.01%, and 0.02% BAK was 105.0%, 90.5%, and 68.7%, respectively, and that of HCO-40 and P-80 was 108.7% and 114.2%, respectively. Conclusion BAK, HCO-40, and P-80 were thought to be involved in corneal injuries caused by each ophthalmic solution. Corneal injuries due to surface action were observed when using HCO-40 and P-80. When HCO-40 was combined with BAK, it induced micellar BAK and reduced corneal injuries by BAK.

Vitreous and aqueous penetration of orally and topically administered moxifloxacin.

Aim: It was the aim of this study to compare the pharmacokinetics of moxifloxacin (MFLX) hydrochloride in rabbits after topical and oral administration. Methods: Three 50-µl applications of MFLX (0.5%) topical ophthalmic solution were instilled into the cul-de-sac of New Zealand white rabbits at 15-min intervals. Aqueous and vitreous samples were collected and analyzed 30–240 min after the final instillation. Assays were performed using high-performance liquid chromatography. MFLX (16 mg/kg of body weight) was administered orally. Drug concentrations in aqueous, vitreous and serum samples, collected at 30–360 min after administration, were determined using high-performance liquid chromatography. Results: After topical administration, the maximum concentrations of MFLX in the aqueous and vitreous samples were 10.2 ± 1.6 µg/ml (30 min; n = 6) and 0.10 ± 0.03 µg/ml (30 min; n = 6), respectively. After oral administration, the maximum concentrations in the aqueous, vitreous and serum samples were 0.9 ± 0.3 µg/ml (120 min; n = 6), 0.7 ± 0.2 µg/ml (240 min; n = 6) and 1.6 ± 0.9 µg/ml (120 min; n = 6), respectively. The percentages of serum MFLX concentration in the aqueous and vitreous samples after oral administration were 55.2 and 41.7%, respectively. Conclusions: The aqueous concentration of MFLX was about 10-fold higher after topical than after oral administration. However, intravitreal MFLX concentrations after oral administration were about 7-fold higher than those after topical administration. The MFLX concentrations in the aqueous humor following oral administration exceeded the minimum inhibitory concentration for 90% of the bacteria involved in ocular infection.

The role of Prdx6 in the protection of cells of the crystalline lens from oxidative stress induced by UV exposure

PurposeThe immediate aim of this study was to investigate alterations in peroxiredoxin (Prdx) 6 at posttranslational levels, and the levels of protein oxidation, lipid peroxidation, and reactive oxygen species (ROS) in lens epithelial cells (LECs) after exposure to severe oxidative stress, such as ultraviolet-B (UV-B). Our ultimate aim was to provide new information on antioxidant defenses in the lens and their regulation, thereby broadening existing knowledge of the role of Prdx6 in lens physiology and pathophysiology.MethodsThe expression of the hyperoxidized form of Prdx6 and oxidation of protein were analyzed by western blotting and the OxyBlot assay in human LECs (hLECs). ROS levels were quantified using DCFH-DA dye, and cell viability was quantified by the MTS and TUNEL assays. To evaluate the protective effect of Prdx6, we cultured lenses with or without the TAT transduction domain (TAT-HA-Prdx6) and observed (and photographed) the cultures at specified time-points after the exposure to UV-B for the development of opacity.ResultsPrdx6 in hLECs was hyperoxidized after exposure to high amounts of UV-B. UV-B treatment of hLECs increased the levels of cell death, protein oxidation, and ROS. hLECs exposed to UV-B showed higher levels of ROS, which could be reduced by the application of extrinsic TAT-HA-Prdx6, attenuating UV-B-induced lens opacity and apoptotic cell death.ConclusionExcessive oxidative stress induces the hyperoxidation of Prdx6 and may reduce the ability of Prdx6 to protect LECs against ROS or stresses. Because extrinsic Prdx6 could attenuate UV-B-induced abuse, this molecule may have a potential in preventing cataractogenesis.

Optical simulation for subsurface nanoglistening

Purpose To determine whether subsurface nanoglistening in hydrophobic acrylic intraocular lenses (IOL) diminishes visual performance. Setting Department of Ophthalmology, Kanazawa Medical University, Uchinada, Ishikawa, Japan. Design Experimental study. Methods The effect of subsurface nanoglistenings was simulated using optical design software Lighttools and Code V with the Liou‐Brenann model eye and an acrylic IOL. Peak irradiance of the retina, forward light scattering, and modulation transfer function (MTF) were evaluated. During optical simulation, particle diameters were set at 100 nm, 150 nm, and 200 nm and volume ratios at 0%, 0.05%, 0.1%, 0.2%, 0.5%, and 1.0%. Results Peak irradiance decreased as subsurface nanoglistening volume ratio and particle size increased. At a volume ratio of 0.05%, the peak irradiance of subsurface nanoglistening particles 100 nm, 150 nm, and 200 nm in diameter decreased 0.7%, 1.8%, and 2.9%, respectively, compared with those at volume ratio 0% (no subsurface nanoglistenings). At a volume ratio of 0.1%, the peak irradiance of subsurface nanoglistening particles 100 nm, 150 nm, and 200 nm decreased 1.5%, 3.6%, and 5.7%, respectively. Forward light scattering increased with increased size of subsurface nanoglistening particle and volume ratio. The MTF was not altered by changes in subsurface nanoglistening particle size or volume ratio. Conclusions Subsurface nanoglistenings increased forward scattering slightly and reduced irradiance but significantly diminished retinal image. The effect of subsurface nanoglistenings on visual function in the absence of severe retinal disease was minimal. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.

Solitary neurofibroma without neurofibromatosis in the superior tarsal plate simulating a chalazion

Dear Editor, Neurofibroma usually appears together with café au lait spots, iris nobules, and other tumors within the scope of neurofibromatosis von Recklinghausen type 1. Solitary neurofibroma is rare, especially in the eyelids, conjunctiva [1–3] or orbit [4]. Among the few reports of isolated neurofibroma in eyelids and conjunctiva there have been just two Japanese cases. One was a 72-year-old female, where a small tumor in the left upper eyelid margin recurred despite repeated resections. The other was a 60-year-old male with two isolated tumors in the lateral canthus and bulbar conjunctiva which bulged spherically. Among the important differential diagnoses we have to think about a chalazion, a meibomian gland ademocarcinoma and a schwannoma [5–7]. This article describes the first case of isolated neurofibroma in the eyelid tarsal plate, and a characteristic useful for diagnosis. The patients medical history, pathological findings, treatment, and outcome are discussed. A 57-year-old woman presented to our institution in November 2007 with a 5-year history of progressive right upper eyelid swelling. She had suffered from malignant lymphoma (diffuse large B-cell lymphoma) 4 years previously, with complete remission following a course of chemotherapy. On ocular examination, no other abnormalities were evident. The external inspection revealed a slightly spherically bulged tumor of the upper eyelid that resembled a chalazion covered by normal-looking skin (Fig. 1a), a characteristic oval-shaped yellowish tumor with numerous centripetal vessels present in the conjunctiva on the inside of the lid (Fig. 1b). Fluorescein staining revealed the tumor elevated from the tarsal plate surrounded by a shallow furrow (Fig. 1c). The tumor, 4× 5 mm in diameter and 1 mm in thickness, had an elastic hard texture. A biopsy showed no evidence of malignant lymphoma. The findings were compatible with neurofibroma, apart from lack of von Recklinghausen disease indicators such as café-au-lait spots, iris nodules or other neurofibromas. To relieve discomfort of compression, in May 2008 the tumor was resected en bloc, and remaining tarsal and palpebral soft tissues were sutured without lid deformity. Hematoxylin and eosin staining revealed that the tumor occupied the full thickness of the tarsal plate, surrounded by normal acini of the meibomian glands. The tumor was covered by a normal palpebral conjunctival epithelium (Fig. 2a). Numerous cells with spindle-shaped nuclei were arranged irregularly (Fig. 2b) in collagen fibers stained blue with Masson’s trichrome. In neurofibroma, S-100 protein positive cells, CD34 positive cells, and mast cells are usually intermingled in various proportions. These cell types were present in this case (two are shown in Fig. 2c,d); accordingly, solitary neurofibroma Presentation at a conference: The 62 Annual Congress of Japan Clinical Ophthalmology (2008)

In vitro and in vivo corneal effects of latanoprost combined with brimonidine, timolol, dorzolamide, or brinzolamide

To examine the relevance of concentration of benzalkonium chloride (BAK) on the cornea, we investigated the effects of latanoprost containing BAK alone and in combination with other antiglaucoma drug classes on corneal epithelium in vitro in a cultured rabbit corneal cell line (SIRC) and in vivo, using a corneal resistance device (CRD). [In vitro] statens seruminstitut rabbit corneal cells were exposed to 0.005% latanoprost for 30s, followed by either phosphate buffered saline (control), 0.1% brimonidine, 0.5% timolol, 1% dorzolamide, or 1% brinzolamide. The number of viable cells was counted at 8, 15, and 30min. [In vivo] Albino rabbits were administered one drop of 0.005% latanoprost, followed 5min later by one drop of an agent from the in vitro trial. This was repeated every 15min for a total of three times. The change in corneal barrier function was assessed by measuring the corneal resistance at 2 and 30min after the final administration. [In vitro] At 8min, the viable cell count in the latanoprost+dorzolamide group was significantly lower than in the control group. At 15 and 30min, all treatment groups, except the latanoprost+brimonidine group, demonstrated significantly lower viable cell counts than the control group. [In vivo] At 2min after the final eye drop, the latanoprost+timolol group and the latanoprost+brinzolamide group demonstrated significantly lower corneal resistance than did the latanoprost+brimonidine group. No significant difference was observed between the agents at 30min. In conclusion, when combining latanoprost containing benzalkonium chloride with other classes of antiglaucoma drugs, brimonidine may cause the least corneal damage, and the number of drug administrations may be an important factor.