Pharmacology of Corticosteroids for Diabetic Macular Edema

Abstract

Purpose: Corticosteroids remain the mainstay of treatment for inflammatory diseases almost 80 years after their first clinical use. Topical ophthalmic formulations of corticosteroids have been available to treat disease of the anterior segment of the eye, but the approval of corticosteroids to treat vitreoretinal diseases, including vein occlusion, diabetic macular edema, and uveitis, has occurred only recently. Although most diseases respond to corticosteroid therapy, some patients are resistant to this therapy and side effects, including cataract and elevated intraocular pressure, can limit their use. The purpose of this review is to detail the basic science of corticosteroids focusing on differences in potency, drug delivery, pharmacokinetics, and gene activation, and how these differences affect safety and efficacy in the treatment of diabetic macular edema.

Methods: A review was conducted of basic science and pharmacology of the corticosteroids used to treat diabetic macular edema.

Results: Clinically available corticosteroids not only have differing potency and pharmacokinetics, but also activate different genes in different target tissues. These differences are associated with distinct efficacy, pharmacokinetic, and safety profiles. It is important to understand these differences in selecting corticosteroids to treat diabetic macular edema.

Conclusions: Recent advances in our understanding of the basic science of corticosteroids can explain clinical differences in these agents regarding efficacy and safety. Importantly, this understanding should allow the future discovery of additional novel corticosteroids to treat diabetic macular edema.

Figure 1

Molecular structures of corticosteroids used in the treatment of vitreoretinal diseases (from http://www.chemspider.com/Chemical-Structure.5541.html, http://www.chemspider.com/Chemical-Structure.5980.html, and http://www.chemspider.com/Chemical-Structure.6196.html; available in the public domain. Accessed March 24, 2016).

Figure 2

Intravitreal pharmacokinetics of corticosteroids. (A) Pharmacokinetics of dexamethasone implant in monkeys. Reprinted from Chang-Lin J-E, Attar M, Acheampong AA, et al. Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci. 2011;52:80–86. © 2011 Association for Research in Vision and Ophthalmology. (B) Pharmacokinetics of fluocinolone acetonide 0.19 mg implant in rabbits (data from Kane et al.). (C) Pharmacokinetics of triamcinolone acetonide 6 mg in rabbits (data from Kamppeter et al.). VH, vitreous humor with or without implant in the sample.

Figure 3

Aqueous pharmacokinetics of fluocinolone acetonide following intravitreal administration of fluocinolone acetonide insert or 0.59 mg implant in humans. Data from Campochiaro et al.

Figure 4

Human GR domain structure and sites of post-translational modification. Reprinted from Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol. 2013;132:1033–1044. Published by Elsevier. The regions of the receptor involved in transactivation (AF1 and AF2), dimerization, nuclear localization, and hsp90 binding are indicated, as are the sites modified by phosphorylation (P), sumoylation (S), ubiquitination (U), and acetylation (A).

Figure 5

Venn diagrams showing GR ligand-specific differential gene expression in studies using microarray gene profiling. (A) Genes differentially expressed after 12 hours of exposure of human trabecular meshwork cells to 0.1 mg/mL TA, 1 mg/mL TA, or 100 nM DEX. Reprinted from Fan BJ, Wang DY, Tham CCY, Lam DSC, Pang CP. Gene expression profiles of human trabecular meshwork cells induced by triamcinolone and dexamethasone. Invest Ophthalmol Vis Sci. 2008;49:1886–1897. © 2008 Association for Research in Vision and Ophthalmology. (B) Genes differentially expressed after 24 hours of exposure of human trabecular meshwork 86 or 93 cells to 1 μM DEX, FA, or TA. Reprinted from Nehmé A, Lobenhofer EK, Stamer WD, Edelman JL. Glucocorticoids with different chemical structures but similar glucocorticoid receptor potency regulate subsets of common and unique genes in human trabecular meshwork cells. BMC Med Genomics. 2009;2:58. Published under a Creative Commons Attribution License.

Figure 6

Mobility of ligand-bound human GR tagged with yellow fluorescent protein in transiently transfected COS-1 cells. (A) Translocation of bound GR into the nucleus is dependent on the steroid and its concentration. (B) The mobility of ligand-bound GR within the nucleus as measured with the recovery of fluorescence after photobleaching also is dependent on the steroid and its concentration. (C) The GR demonstrates different mobility in cells exposed to 1 μm DEX versus 1 μm TA or corticosterone. Adapted from Schaaf MJM, Cidlowski JA. Molecular determinants of glucocorticoid receptor mobility in living cells: the importance of ligand affinity. Mol Cell Biol. 2003;23:1922–1934. © 2003 American Society for Microbiology.