John C. Lang

Ocular drug delivery conventional ocular formulations

Abstract Within the last few decades, in response to the advent of potent and versatile therapeutic agents, the diversity of conventional ophthalmic formulations has gradually evolved, extending well beyond simple solutions, and now includes a variety of types of drug administration. In most recent publications, authors have broadened the notion of conventional ophthalmic delivery systems to encompass more than simple solutions and suspensions [1]. While not strictly ‘conventional’, the ready availability of several commonly used drug vehicles suggests they have achieved acceptance, have been elevated to the category of conventional, and will be considered in this comparison. In this article, I have summarized the types of commonly used ophthalmic formulations, indicated the generality of their applicability and acceptance, differentiated their characteristics and utility, and projected anticipated use and development in the decade to come. This should also serve to put into perspective the discussions of more sophisticated components and elaborations described in this issue.

Modulation of oxidative stress responses in the human retinal pigment epithelium following treatment with vitamin C.

Oxidative stress (OS) in the retina plays an important role in the development and progression of age‐related macular degeneration (AMD). Our previous work has shown that OS can quantitatively regulate the expression of AP‐1 family genes in the retinal pigment epithelium (RPE). In this study, we sought to determine whether AP‐1 genes can be used as cellular biomarkers of OS to evaluate the efficacy of ascorbate, the major aqueous‐phase antioxidant in the blood, in reducing OS in RPE cells in vitro. Human ARPE19 cells were pretreated with increasing levels of ascorbate (0–500 µM) for 3 days which was then removed from the medium. OS was induced 24 h later by the addition of hydrogen peroxide for 1–4 h, to bring the final media concentration of H2O2 to 500 µM. FosB, c‐Fos, and ATF3 gene expression was examined from 0 to 24 h after OS. Pretreatment with 200 µM ascorbate maximally reduced the transcriptional OS response of AP‐1 genes by up to 87% after 1 and 4 h, compared to controls. One hundred micromolar of ascorbate provided a statistically significant, but far more modest effect. Ascorbate supplementation of 100–200 µM appears to strongly inhibit OS‐induced activation of AP‐1 in vitro, but pretreatment with higher levels of ascorbate conferred no additional advantage. These studies suggest that there are optimal levels of antioxidant supplementation to the RPE in vitro. Laboratory assays based upon transcription factor biomarkers may be useful to define beneficial molecular responses to new antioxidants, alternative dosing regimens, and to explore therapeutic efficacy in OS models in vitro. J. Cell. Physiol. 226: 2025–2032, 2011.

Light-Induced Retinal Degeneration Is Prevented by Zinc, a Component in the Age-related Eye Disease Study Formulation †

Mineral supplements are often included in multivitamin preparations because of their beneficial effects on metabolism. In this study, we used an animal model of light‐induced retinal degeneration to test for photoreceptor cell protection by the essential trace element zinc. Rats were treated with various doses of zinc oxide and then exposed to intense visible light for as long as 8 h. Zinc treatment effectively prevented retinal light damage as determined by rhodopsin and retinal DNA recovery, histology and electrophoretic analysis of DNA damage and oxidized retinal proteins. Zinc oxide was particularly effective when given before light exposure and at doses two‐ to four‐fold higher than recommended by the age‐related eye disease study group. Treated rats exhibited higher serum and retinal pigment epithelial zinc levels and an altered retinal gene expression profile. Using an Ingenuity database, 512 genes with known functional annotations were found to be responsive to zinc supplementation, with 45% of these falling into a network related to cellular growth, proliferation, cell cycle and death. Although these data suggest an integrated and extensive regulatory response, zinc induced changes in gene expression also appear to enhance antioxidative capacity in retina and reduce oxidative damage arising from intense light exposure.

Turbidity investigation of the sol–gel transition in carrageenan gels under physiologic conditions

A spectrophotometer was used to measure the turbidity of a carrageenan gel as a function of temperature. The optical transmission of the gels was found to decrease as the gels undergo the sol–gel phase transition. The differential of transmission (I) with respect to temperature (T), dI/dT, exhibits peaks for both the cooling and the heating runs with the peak positions corresponding to temperatures of gelation and melting, respectively. The full-width at half-height of the dI/dT peak obtained from the heating curve is about 2.5 times broader than that from the cooling curve. This indicates that the melting of gels may involve multiple relaxation mechanisms. The area of the hysteresis loop covered by the cooling and the heating curves increases with a decrease in the scanning rate. The thermal cycling has little impact on the sol–gel transition in the gels. The experiments show that turbidity is a powerful tool for studying the sol–gel transition in carrageenan gels.

Kinetics of ion‐induced gelation in carrageenan gels under physiologic conditions

The kinetics of gelation of an ungelled carrageenan solution exposed to a gel-inducing ionic solution was studied using a turbidity technique. Alkali metal ions were allowed to diffuse through a dialysis membrane into the solution of biopolymer. Optical transmission was measured as a function of distance away from the membrane. In the early stage of 12 h, the transmission increases with distance. After 96 h, the transmission is independent of distance. This indicates that gelation is completed everywhere inside the gel and the gels structure is homogeneous, in agreement with previous results. Time-dependent transmission indicates the presence of two relaxation processes occurring during ion-induced gelation: a primary relaxation process related to the gelling zone movement, and a secondary relaxation process related to local diffusion of polymer, bound ions, and water molecules.