环孢素A缓释系统眼内植入治疗葡萄膜炎的实验研究

Intraocular implantation of cyclosporine A drug delivery system in the treatment of experimental uveitis

目的探讨环孢素A缓释系统(CsA DDS)玻璃体腔植入治疗实验性葡萄膜炎的有效性和安全性。方法43只新西兰白兔中,其中30只建立葡萄膜炎动物模型,按照随机数字表法分为4组,即空白对照组(A)6只、空白DDS植入组(B)6只、CsA口服治疗组(C)6只及CsA DDS植入组(D)12只,于术后不同时间点观察各组兔眼前房闪辉、房水细胞、前房渗出、玻璃体细胞以及玻璃体混浊度并进行分级,并进行视网膜电图(ERG)、眼和肝、肾组织病理学检查;余13只新西兰兔右眼植入CsA DDS,检测玻璃体腔CsA药物浓度。结果(1)30只实验兔均成功诱发葡萄膜炎模型。各时间点A、B、C组各项炎性指标分级均高于D组,A、B组间及C、D组间差异无统计学意义(P>0.05),D组与A、B组间差异有统计学意义(P<0.05);ERG检查显示A、B两组b波波幅降低幅度均较D组明显,差异有统计学意义(P<0.05);A、B组睫状体和视网膜有大量炎性细胞浸润,组织明显破坏,而C、D组则未见炎性细胞浸润,组织结构基本完整。(2)CsA DDS植入术后玻璃体腔药物浓度在1个月时达到(491.0±481.6)ng/ml,2个月时为(575.2±373.2)ng/ml,3个月时缓慢下降至(301.5±128.5)ng/ml。光镜检查未见眼内毒性反应。结论CsA DDS玻璃体腔植入能够在眼内维持安全有效的药物浓度,明显减轻兔眼葡萄膜炎性反应,为葡萄膜炎的治疗提供了一种新的用药途径。

Objective To investigate the effects and safety of cyclosporine A drug delivery system (CsA DDS) implanted into vitreous cavity on the treatment of experimental rabbit uveitis. Methods A model of uveitis was established in 30 New Zealand white rabbits (30 eyes). The rabbits were randomized into control group (group A, 6 eyes) , intravitreal non-medicated DDS group (group B, 6 eyes) , oral CsA group (group C, 6 eyes) and intravitreal CsA DDS group (group D, 12 eyes). The inflammatory parameters such as floating cells, flaring and exudation in anterior chamber were graded. The cells infiltration and degree of opacity in vitreous were scored as well. The electroretinography and histopathological examination in eye, liver and kidney were recorded. In addition, CsA level in vitreous cavity was measured by HPLC in another 13 New Zealand white rabbits that received intravitreal implantation of CsA DDS. Results Uveitis was successfully induced in the 30 eyes. The inflammation in groups A, B and C was more severe than group D. There was no significant difference between groups A and B, between groups C and D ( P > 0.05); there was significant difference between groups D and A or B (P < 0. 05). The electroretinography showed more significant b-wave depression in groups A and B than group D (P < 0.05). A large amount of inflammatory cells infiltration and marked tissue disorganization were found at ciliary body and retina in groups A and B. The mean drug level in vitreous cavity was (491.0± 481.6) ng/ml at 4 weeks, (575.2±373.2) ng/ml at 8 weeks and (301. 5±128. 5) ng/ml at 12 weeks. No toxicity could be detected in histological examination by light microscopy. Conclusions Sustained therapeutic drug level could be achieved by implanting CsA DDS into vitreous cavity. It may effectively reduce the ocular inflammation in the rabbit model of uveitis.