Chennamaneni Srinivas Rao, Bohner Austin, Bernhisel Ashlie, Ambati Balamurali K
Department of Ophthalmology, John A Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, Utah, 84132, USA.
Pharm Res. 2014 Nov;31(11):3179-90. doi: 10.1007/s11095-014-1410-7. Epub 2014 Jun 20.
To advance therapy for the treatment of concurrent uveitis and post-cataract surgical inflammation; we evaluated pharmacokinetics and pharmacodynamics of Bioerodible Dexamethasone Implant (BDI) containing 0.3 mg of dexamethasone (DXM) in Concanavalin A (Con A) induced uveitis followed by phacoemulsification in New Zealand White (NZW) rabbits.
The BDI was implanted in the inferior fornix of the capsular bag after intravitreal injection of Con A and ensuing phacoemulsification in NZW rabbits; standard-of-care topical 0.1% dexamethasone drops served as control. DXM was quantified by liquid chromatography-tandem mass spectrometry and pharmacokinetics of DXM in disease vs. healthy eyes was compared. All eyes were assessed clinically using slit lamp biomicroscopy and Draize scoring scale. Retinal thickness and histological analyses were performed to evaluate retinal edema, inflammation and implant biocompatibility respectively.
In Con A-induced inflammatory uveitic cataract model the BDI controlled anterior and posterior segment inflammation as well as retinal thickening more effectively than topical drops. The exposure (AUC0-t) of DXM with BDI is superior in all ocular tissues, while topical drops did not achieve therapeutic posterior segment levels and did not control inflammation nor prevent retinal edema and architectural disruption.
Our results demonstrate the superiority of the BDI in suppressing Con A-induced inflammation and retinal edema in NZW rabbits and highlight the need for sustained bidirectional delivery of potent anti-inflammatory agents for 5 to 6 weeks to optimize clinical outcomes.
为推进并发性葡萄膜炎和白内障手术后炎症的治疗，我们在新西兰白兔身上，评估了含0.3毫克地塞米松（DXM）的可生物降解地塞米松植入物（BDI）在伴晶状体超声乳化术的刀豆球蛋白A（Con A）诱导性葡萄膜炎中的药代动力学和药效学。
在新西兰白兔玻璃体内注射Con A并随后进行晶状体超声乳化术后，将BDI植入囊袋的下穹窿；使用标准护理的0.1%地塞米松滴眼液作为对照。通过液相色谱-串联质谱法定量DXM，并比较疾病眼与健康眼中DXM的药代动力学。使用裂隙灯生物显微镜检查和Draize评分量表对所有眼睛进行临床评估。分别进行视网膜厚度和组织学分析以评估视网膜水肿、炎症和植入物生物相容性。
在Con A诱导的炎性葡萄膜炎性白内障模型中，BDI比局部滴眼液更有效地控制前段和后段炎症以及视网膜增厚。BDI的DXM暴露量（AUC0-t）在所有眼组织中均更高，而局部滴眼液未达到治疗性后段水平，也未控制炎症，也未预防视网膜水肿和结构破坏。
我们的结果证明了BDI在抑制新西兰白兔Con A诱导的炎症和视网膜水肿方面的优越性，并强调需要持续双向递送强效抗炎药5至6周以优化临床结果。
