School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, P.O.B. 1627, 70211, Kuopio, Finland.
Department of Ophthalmology, Unit of Vitreoretinal Surgery, Helsinki University Central Hospital, and Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.
Sci Rep. 2021 Jan 13;11(1):980. doi: 10.1038/s41598-020-80127-1.
Proliferative vitreoretinopathy (PVR) with rhegmatogenous retinal detachment (RRD) is a complex inflammatory ocular disease. Statins are widely used cholesterol-lowering drugs with putative anti-inflammatory properties. In this study, we have explored their efficacy in controlling post-surgical PVR formation. Simvastatin (SIM), atorvastatin (ATV), or rosuvastatin (RSV) were added to cultures of human retinal pigment epithelial cells (ARPE-19) prior to exposure with the bacterial lipopolysaccharide (LPS), and the production of pro-inflammatory cytokines (IL-6, IL-8, MCP-1) was examined using an enzyme-linked immunosorbent assay. In addition, the concentrations of simvastatin, atorvastatin, rosuvastatin, and their metabolites were measured from the vitreal samples of 20 patients undergoing vitrectomy (16 of them receiving oral statin therapy) using an ultra-performance liquid chromatography-tandem mass spectrometer technique. All statins alleviated LPS-induced inflammation at 5 µM concentration in the ARPE-19 cell cultures. Statin levels in the vitreous samples ranged from 6 to 316 pg/mL (ca. 0.1-7 M). Vitreal statin concentrations were similar to the typical steady-state unbound statin concentrations in plasma, indicating that only the unbound drug distributes from the blood circulation into the vitreous. Pharmacokinetic simulations of the intravitreal delivery of statins indicate that the measured clinical statin concentrations could be maintained with existing drug delivery technologies for months. Our results suggest that intravitreal statin therapy may have the potential in alleviating the risk of post-surgical PVR.
增生性玻璃体视网膜病变（PVR）伴孔源性视网膜脱离（RRD）是一种复杂的炎症性眼病。他汀类药物是广泛应用的降胆固醇药物，具有潜在的抗炎作用。在本研究中，我们探讨了它们在控制术后 PVR 形成中的疗效。在人视网膜色素上皮细胞（ARPE-19）暴露于细菌脂多糖（LPS）之前，加入辛伐他汀（SIM）、阿托伐他汀（ATV）或瑞舒伐他汀（RSV），并用酶联免疫吸附试验检测促炎细胞因子（IL-6、IL-8、MCP-1）的产生。此外，采用超高效液相色谱-串联质谱技术，从 20 名接受玻璃体切除术的患者（其中 16 名接受口服他汀类药物治疗）的玻璃体样本中测量了辛伐他汀、阿托伐他汀、瑞舒伐他汀及其代谢物的浓度。所有他汀类药物在 ARPE-19 细胞培养物中均能在 5µM 浓度下缓解 LPS 诱导的炎症。玻璃体样本中的他汀类药物浓度范围为 6 至 316pg/mL（约 0.1-7µM）。玻璃体中他汀类药物浓度与血浆中典型的稳态游离他汀类药物浓度相似，表明只有游离药物从血液循环分布到玻璃体中。他汀类药物玻璃体内给药的药代动力学模拟表明，现有的药物输送技术可以在数月内维持测量的临床他汀类药物浓度。我们的研究结果表明，玻璃体内他汀类药物治疗可能有潜力降低术后 PVR 的风险。
