PURPOSE. To develop pharmacokinetics models to describe the disposition of small lipophilic molecules in the cornea and retina after periocular (subconjunctival or posterior subconjunctival) administration. METHODS. Compartmental pharmacokinetics analysis was performed on the corneal and retinal data obtained after periocular administration of 3 mg of celecoxib (a selective COX-2 inhibitor) to Brown Norway (BN) rats. Berkeley Madonna, a differential and difference equation-based modeling software, was used for the pharmacokinetics modeling. The data were fit to different compartment models with first-order input and disposition, and the best fit was selected on the basis of coefficient of regression and Akaike information criteria (AIC). The models were validated by using the celecoxib data from a prior study in Sprague-Dawley (SD) rats. The corneal model was also fit to the corneal data for prednisolone at a dose of 2.61 mg in albino rabbits, and the model was validated at two other doses of prednisolone (0.261 and 26.1 mg) in these rabbits. Model simulations were performed with the finalized model to understand the effect of formulation on corneal and retinal pharmacokinetics after periocular administration. RESULTS. Celecoxib kinetics in the BN rat cornea can be described by a two-compartment (periocular space and cornea, with a dissolution step for periocular formulation) model, with parallel elimination from the cornea and the periocular space. The inclusion of a distribution compartment or a dissolution step for celecoxib suspension did not lead to an overall improvement in the corneal data fit compared with the two-compartment model. The more important parameter for enhanced fit and explaining the apparent lack of an increase phase in the corneal levels is the inclusion of the initial leak-back of the dose from the periocular space into the precorneal area. The predicted celecoxib concentrations from this model also showed very good correlation (r = 0.99) with the observed values in the SD rat corneas. Similar pharmacokinetics models explain drug delivery to the cornea in rat and rabbit animal models. Retinal pharmacokinetics after periocular drug administration can be explained with a four-compartment (periocular space, choroid-containing transfer compartment, retina, and distribution compartment) model with elimination from the periocular space, retina, and choroid compartment. Inclusion of a dissolution-release step before the drug is available for absorption or elimination better explains retinal tmax. Good fits were obtained in both the BN (r = 0.99) and SD (r = 0.99) rats for retinal celecoxib using the same model; however, the parameter estimates differed. CONCLUSIONS. Corneal and retinal pharmacokinetics of small lipophilic molecules after periocular administration can be described by compartment models. The modeling analysis shows that (1) leak-back from the site of administration most likely contributes to the apparent lack of an increase phase in corneal concentrations; (2) elimination via the conjunctival or periocular blood and lymphatic systems contributes significantly to drug clearance after periocular injection; (3) corneal pharmacokinetics of small lipophilic molecules can be explained by using similar models in rats and rabbits; and (4) although there are differences in some retinal pharmacokinetics parameters between the pigmented and nonpigmented rats, the physiological basis of these differences has yet to be ascertained.
Objective: To evaluate the impact on visual acuity of reducing or abandoning patching therapy during the first six years of life after early unilateral cataract surgery.
Methods: We reviewed the medical records of nine children with unilateral congenital cataracts who underwent cataract surgery when ≤6 weeks of age. All had good compliance with optical correction until 6 years of age and patching therapy until at least 12 months of age.
Results: The children underwent cataract surgery at a mean age of 21.7 ± 9.5 days. At 12 months of age the children were patched a mean of 6.7 ± 2.4 hours/day. Patching compliance declined steadily thereafter. By 6 years of age, they were only being patched a mean of 1.7 ± 2.0 hours/day. Four children abandoned patching prior to the 6 year exam; the acuities improved or remained the same for three of these children, but worsened for one child by two lines.
Conclusion: Visual acuity remained relatively stable even when patching therapy was reduced or abandoned by children ≤ 6 years of age provided cataract surgery was performed during early infancy, an optical correction was consistently worn and there was good compliance with patching therapy during early childhood.
Purpose: To analyze the visual outcomes and method of final visual correction in eyes with corneal ectasia after laser in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK).
Setting: Emory University Department of Ophthalmology and Emory Vision, Atlanta Georgia, USA.
Methods: This retrospective review comprised 74 eyes of 45 patients with corneal ectasia after LASIK (72 eyes) or PRK (2 eyes). Outcomes included postoperative uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), best corrected visual acuity (BCVA), and refraction; method of final visual correction; and time to rigid gas-permeable (RGP) contact lens failure.
Results: Corneal ectasia developed a mean of 19.2 months after surgery. Postoperatively, the mean UCVA was 20/400, the mean BSCVA before ectasia management was 20/108, and the mean BCVA was 20/37. After ectasia management, the final BCVA was 20/40 or better in 78% of eyes. Final visual correction was achieved with RGP lenses in 77% of eyes, spectacles in 9%, collagen crosslinking in 3%, intracorneal ring segments in 1%, and penetrating keratoplasty (PKP) in 8%. Two eyes with intracorneal ring segments required segment explantation and subsequent PKP. One eye that had PKP had a graft-rejection episode; there were no graft failures. Two eyes (3%) did not require a visual device to improve visual acuity. The mean time to successful RGP lens wear was 24.8 months; 80% of cases initially managed with RGP lenses were successful with this form of treatment.
Conclusions: The majority of eyes developing postoperative corneal ectasia achieved functional visual acuity with RGP lens wear and did not require further intervention. Penetrating keratoplasty can usually be postponed or avoided by alternative methods of visual rehabilitation; however, PKP, when necessary, can provide good visual outcomes.
Purpose: To determine the effect of different blades on laser in situ keratomileusis (LASIK) flap thickness created with the Amadeus I microkeratome (Ziemer Ophthalmic Systems).
Setting: Emory University Department of Opthalmology and Emory Vision, Atlanta, Georgia, USA.
Methods: This retrospective nonrandomized comparative case study from January 2005 through June 2006 compared LASIK flap thickness created with blades from 2 manufacturers: the Surepass from Surgical Instrument Systems and distributed by AMO and the ML7090 CLB distributed by Med-Logics, Inc. Sex, preoperative corneal thickness, surgical-eye sequence, flap thickness and variance, and residual stromal bed were evaluated in each group.
Results: This study evaluated 424 eyes of 226 patients. Surepass blades were used in 238 eyes and ML7090 CLB blades in 186 eyes. There were no significant differences between the 2 blade groups in preoperative corneal thickness, sex, or cases with corneal thickness greater than 550 µm. Mean flap thickness and variance were significantly lower in the ML7090 CLB group than in the Surepass group (P<.0001). There were no significant differences in flap thickness in either group based on sex; however, in both groups, flap thickness was significantly lower in second eyes and in eyes with a preoperative thickness less than 550 µm (P<.001).
Conclusions: The Amadeus I microkeratome created thinner, more consistent LASIK flaps with the ML7090 CLB blade than with the Surepass blade. Preoperative corneal thickness and eye sequence affected flap thickness, while sex did not.
Many aspects of photoreceptor metabolism are regulated as diurnal or circadian rhythms. The nature of the signals that drive rhythms in mouse photoreceptors is unknown. Dopamine amacrine cells in mouse retina express core circadian clock genes, leading us to test the hypothesis that dopamine regulates rhythms of protein phosphorylation in photoreceptor cells. To this end, we investigated the phosphorylation of phosducin, an abundant photoreceptor-specific phosphoprotein. In mice exposed to a daily light-dark cycle, robust daily rhythms of phosducin phosphorylation and retinal dopamine metabolism were observed. Phospho-phosducin levels were low during the daytime and high at night, and correlated negatively with levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid. The effect of light on phospho-phosducin levels was mimicked by pharmacological activation of dopamine D4 receptors. The amplitude of the diurnal rhythm of phospho-phosducin was reduced by more than 50% in D4 receptor knockout mice, due to higher daytime levels of phospho-phosducin. In addition, the daytime level of phospho-phosducin was significantly elevated by L-745,870, a dopamine D4 receptor antagonist. These data indicate that dopamine and other light-dependent processes cooperatively regulate the diurnal rhythm of phosducin phosphorylation. Under conditions of constant darkness, a circadian rhythm of phosducin phosphorylation was observed, which correlated negatively with a circadian rhythm of 3,4-dihydroxyphenylacetic acid level. The circadian fluctuation of phospho-phosducin was completely abolished by constant infusion of L-745,870, indicating that the rhythm of phospho-phosducin level is driven by dopamine. Thus, dopamine release in response to light and circadian clocks drives daily rhythms of protein phosphorylation in photoreceptor cells.
Purpose. Nob mice share the same mutation in the Nyx gene that is found in humans with complete congenital stationary night blindness (CSNB1). Nob mutant mice were studied to determine whether this defect resulted in myopia, as it does in humans. Methods. Refractive development was measured in unmanipulated wild-type C57BL/6J (WT) and nob mice from 4 to 12 weeks of age by using an infrared photorefractor. The right eye was form deprived by means of a skull-mounted goggling apparatus at 4 weeks of age. Refractive errors were recorded every 2 weeks after goggling. The content of dopamine and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were measured by HPLC with electrochemical detection (HPLC-ECD) in retinas of nob and WT mice under light- and dark-adapted conditions. Results. The nob mice had greater hyperopic refractive errors than did the WT mice under normal visual conditions, until 12 weeks of age when both strains had similar refractions. At 6 weeks of age, refractions became less hyperopic in the nob mice but continued to become more hyperopic in the WT mice. After 2 weeks of form deprivation (6 weeks of age), the nob mice displayed a significant myopic shift (∼4 D) in refractive error relative to the opposite and control eyes, whereas WT mice required 6 weeks of goggling to elicit a similar response. As expected with loss of ON pathway transmission, light exposure did not alter DOPAC levels in the nob mice. However, dopamine and DOPAC levels were significantly lower in the nob mice compared with WT. Conclusions. Under normal laboratory visual conditions, only minor differences in refractive development were observed between the nob and WT mice. The largest myopic shift in the nob mice resulted after form deprivation, suggesting that visual pathways dependent on nyctalopin and/or abnormally low dopaminergic activity play a role in regulating refractive development. These findings demonstrate an interaction of genetics and environment in refractive development.
by
Ji-Jing Pang;
Sanford L. Boye;
Ashok Kumar;
Astra Dinculescu;
Wentao Deng;
Jie Li;
Qiuhong Li;
Asha Rani;
Thomas C. Foster;
Bo Chang;
Norman L. Hawes;
Jeffrey Boatright;
William W. Hauswirth
PURPOSE. To test AAV-mediated gene therapy in the rd10 mouse, a natural model of recessive RP caused by mutation of the β-subunit of rod photoreceptor cGMP phosphodiesterase.
METHODS. One eye of a cohort of rd10 mice kept in a dark environment was subretinally injected at postnatal day (P) 14 with 1 μL AAV5-smCBA-PDEβ. The contralateral eye was not injected. The animals were then maintained for 2 weeks in the dark before they were moved to a normal 12-hour light/12-hour dark cycling light environment for visually guided behavioral training. Three weeks after injection, treated rd10 mice were examined by scotopic and photopic electroretinography and then killed for biochemical and morphologic examination.
RESULTS. Substantial scotopic ERG signals were maintained in treated rd10 eyes, whereas untreated eyes in the same animals showed minimal signals. Treated eyes showed photopic ERG b-wave amplitudes similar to those of the normal eyes; in untreated partner eyes, only half the normal amplitudes remained. Strong PDEβ expression was observed in photoreceptor outer segments only in treated eyes. Light microscopy showed a substantial preservation of the outer nuclear layer in most parts of the treated retina only. Electron microscopy showed good outer segment preservation only in treated eyes. A visually guided water maze behavioral test under dim light showed significantly improved performance in one eye-treated rd10 mice compared with untreated mice.
CONCLUSIONS. These data demonstrate that P14 administration of AAV5-smCBA-PDEβ can prevent retinal degeneration in rd10 mice, as reflected by significant structural, biochemical, electrophysiological, and behavioral preservation/restoration. These results serve as a baseline for studying long-term retinal rescue in rd10 mice.
Objective: To report the clinicopathologic features of 2 patients with carcinosarcoma of the orbit.
Design: Case reports.
Participants: Two patients with orbital carcinosarcoma were identified.
Methods: Retrospective chart review with clinicopathologic correlation and literature review.
Main Outcome Measures: Clinical examination, imaging studies, and histopathologic findings.
Results: Two patients, a 56-year-old woman and a 91-year-old woman, with orbital carcinosarcoma were identified. Both tumors contained sarcomatous and carcinomatous components and invaded periorbital structures.
Conclusions: Carcinosarcoma may arise in the orbit or extend into the orbit from the paranasal sinuses. This malignant neoplasm should be aggressively treated with a combination of surgical resection, chemotherapy, and radiation therapy.
Purpose
Retinitis Pigmentosa (RP) is a progressive neurodegenerative disease resulting in blindness for which there is no current treatment. While the members of the family of RP diseases differ in etiology, their outcomes are the same: apoptosis of rods followed by cones. Recently, the bile acid, tauroursodeoxycholic acid (TUDCA), has been shown to have anti-apoptotic properties in neurodegenerative diseases, including those of the retina. In this study we examine the efficacy of TUDCA on preserving rod and cone function and morphology at post-natal day 30 (P30) in the rd10 mouse, a model of RP.
Methods
Wild-type C57BL/6J and rd10 mice were systemically injected with TUDCA (500 mg/kg) every three days from P6-P30 and compared to vehicle (0.15M NaHCO3). At P30, retinal function was measured with electroretinography (ERG) and morphological preservation of the rods and cones assessed with immunohistochemistry.
Results
Dark-adapted ERG responses were two-fold greater in rd10 mice treated with TUDCA compared to vehicle, while light-adapted responses were two-fold larger in TUDCA-treated mice compared to controls, at the brightest ERG flash intensities. TUDCA-treated rd10 retinas had five-fold more photoreceptors than vehicle-treated. TUDCA treatments did not alter retinal function or morphology of wild-type mice when administered to age-matched mice.
Conclusions
TUDCA is efficacious and safe in preserving vision in the rd10 mouse model of RP when treated between P6 and P30. At P30, a developmental stage at which nearly all rods are absent in the rd10 mouse model of RP, TUDCA treatment preserved both rod and cone function and greatly preserved overall photoreceptor numbers.