二性霉素B眼内缓释系统对白色念珠菌性眼内炎影响的实验研究

Anti-infectious effect of sustained antravitreal amphotericin B drug delivery system on experimental rabbit fungal endophthalmitis of Candida albicans

目的探讨二性霉素B眼内缓释系统对兔实验性白色念珠菌性眼内炎的治疗作用及其安全性。方法缓释系统由二性霉素B和乙交酯丙交酯己内酯三元共聚物(PGLC)制成。(1)药效学实验:50只新西兰兔右眼行中央部玻璃体切除,同时眼内注射104cfu/ml白色念珠菌悬液0.1ml,构建眼内炎模型后,随机数字表法分为5组,每组10只眼。A组,眼内炎对照组;B组,空白药物载体组;C组,二性霉素B眼液滴眼组;D组,二性霉素B眼内注射组;E组,二性霉素B眼内缓释系统组。对比观察各组眼内炎性反应。高效液相色谱分析方法定期检测眼内二性霉素B浓度。(2)毒性实验:20只正常新西兰兔分为3组:正常对照组,2只眼;DDS组,眼内植入1粒含药1mg的缓释系统,10只眼;空白载体组,眼内植入空白药物载体,8只眼。分别进行视网膜电图、眼部病理学及透射电镜检查,并行肝、肾病理学检查。结果E组在各个时间点玻璃体混浊较A、B、C组均明显减轻;E组与D组玻璃体混浊在2周内无差异,其后存在差异;D组玻璃体混浊在2周内与A、B、C组存在差异,但2周后无差异;C组在各个时间点玻璃体混浊较A、B组均无显著差异。眼内植入药物缓释系统后,视网膜电图无显著改变,视网膜病理学和电镜检查以及肝、肾病理学检查未见异常改变。结论二性霉素B眼内缓释系统能够抑制白色念珠菌性眼内炎进展。PGLC缓释系统释药稳定、安全、无毒性。

Objective To evaluate the efficacy and toxicity of sustained intravitreal amphotericin B drug delivery system （DDS） on experimental rabbit fungal endophth-lmitis of Candida albieans. Methods Fifty New Zealand rabbits received central vitrectomy were followed by Candida albicans suspension （ 104 colony forming unit, cfu） injection. Rabbits were grouped randomly into five with ten in each as follows： Group A, endophthalmitis control group; Group B, DDS of vehicle alone; Group C, topical treatment with amphotericin B eyedrop; Group D, 5μg of amphotericin B intravitreal injection every week for two weeks; Group E, DDS contained 1 mg of amphotericin B. Slit-lamp and indirect-ophthalmoscope were performed at different time for two months and vitreous opacity was compared between each group. The intraocular drug concentration was measured with high performance liquid chromatography （HPLC）. Light and electron microscope were conducted to evaluate the toxicity of DDS and the effect of vehicle on intraocular structure. Electroretinography （ERG） was employed to evaluate the function of retina before and after the implantation of DDS. Results Endophthalmitis was obviously inhibited in group E while vitreous was still opacity in other groups. The drug concentration in vitreous cavity was stable and remained for two months in group E while rapidly went down two weeks later in group D. No toxic evidence was found in ocular, liver and kidney tissue and retinal ultrastructure was normal. There was no difference in ERG study before and after the DDS was implanted. Conclusions Sustained intravitreal amphotericin B DDS can significantly suppress the formation of fungal colony and inhibit the development of infection with long and stable intraocular drug concentration maintenance. The vehicle and amphotericin B DDS are safe to intraocular structure. （Chin J Ophthalmol, 2006, 42 ： 420-425）