Drug Discovery, Retinal Therapeutics, Allergan Inc., Irvine, CA, USA.
Ophthalmologica. 2010;224 Suppl 1:25-30. doi: 10.1159/000315158. Epub 2010 Aug 18.
Natural corticosteroids (e.g. hydrocortisone) and synthetic selective glucocorticoid (GC) agonists have been used by ophthalmologists for decades to treat various forms of ocular inflammation. More recently, increased clinical use of locally delivered GC has shown significant benefit for the treatment of multiple retinal indications including macular edema associated with uveitis, retinal vascular occlusions and diabetes. Our current understanding of the clinical utility of specific intraocular GC far surpasses our knowledge of their biologic and pharmacologic activities in the eye.
To present an update on GC receptor (GR) biology in general and as it applies to the eye, and discuss the pharmacokinetics, delivery and pharmacology of the commonly used intraocular GC dexamethasone (DEX), triamcinolone acetonide (TA) and fluocinolone acetonide (FA).
DEX, TA and FA are structurally similar but significantly differentiated by their aqueous and lipid solubility, delivery system requirements, pharmacokinetics and interactions with functional GR. Culture of human trabecular meshwork cells and full transcriptome microarray analysis reveals that DEX, TA and FA generate unique gene transactivation and repression profiles as well as potentially distinct biologic responses that are not only steroid structure dependent, but also dose and time dependent. Finally, DEX and FA markedly protect photoreceptors from degenerating in animal models of excessive light and retinitis pigmentosa, respectively.
It is tempting to speculate that the unique pharmacokinetic and pharmacologic profiles of the commonly used intraocular steroids and novel future drugs may reveal significant differences in their therapeutic value in patients with macular edema or other inflammatory disease, in their ocular adverse side effect profile, and their ability to normalize glial and neuronal function in diseased retina.
天然皮质类固醇（例如氢化可的松）和合成选择性糖皮质激素（GC）激动剂已被眼科医生使用了数十年，用于治疗各种形式的眼部炎症。最近，局部给予 GC 的临床应用增加表明，其对多种视网膜适应症具有显著益处，包括与葡萄膜炎相关的黄斑水肿、视网膜血管闭塞和糖尿病。我们目前对特定眼内 GC 的临床应用的了解远远超过了我们对其在眼部的生物学和药理学作用的了解。
介绍 GC 受体（GR）生物学的最新进展，以及其在眼部的应用，并讨论常用的眼内 GC 地塞米松（DEX）、曲安奈德（TA）和氟轻松（FA）的药代动力学、递送和药理学。
DEX、TA 和 FA 在结构上相似，但在水溶解度和脂溶解度、递送系统要求、药代动力学以及与功能性 GR 的相互作用方面存在显著差异。人眼小梁细胞的培养和全转录组微阵列分析表明，DEX、TA 和 FA 产生独特的基因转录激活和抑制谱，以及潜在的不同生物学反应，这些反应不仅取决于类固醇结构，还取决于剂量和时间。最后，DEX 和 FA 分别在光毒性和色素性视网膜炎的动物模型中明显保护光感受器免受变性。
人们不禁推测，常用的眼内类固醇和新型未来药物的独特药代动力学和药理学特征可能会揭示它们在治疗黄斑水肿或其他炎症性疾病患者方面的治疗价值、眼部不良反应谱以及在疾病视网膜中恢复神经胶质和神经元功能的能力方面存在显著差异。
