【作者】 刘爱明；

【导师】 吕志华；

【作者基本信息】 中国海洋大学 ， 生药学， 2005， 硕士

【摘要】 环孢素A是自真菌培养液中分离获得的中性环状十一肽化合物,具有强烈的选择性免疫抑制活性,自从1978年首次应用于临床以来,目前已广泛用于防治同种器官移植免疫排斥反应以及其它多种自身免疫性疾病。 葡萄膜炎可以累及葡萄膜、视网膜、玻璃体,并多与免疫因素有关,已有的研究表明环孢素A对葡萄膜炎有确切的治疗作用。 本文首先探讨了兔眼葡萄膜炎动物模型的构建,并以分枝结核杆菌H37Ra抗原为免疫原,对新西兰大白兔进行足底免疫、眼内初次免疫、眼内加强免疫构建葡萄膜炎动物模型、并模拟葡萄膜炎复发。文献所载作为分析方法金标准的HPLC在环孢素A血药浓度监测中,其方法最低定量限在基于2mL血液时多在50ng·mL^-1,这样的灵敏度不适用于小体积低浓度生物标本兔眼玻璃体中环孢素A的检测,为此本文进一步多角度优化色谱条件,显著提高了检测灵敏度,使该方法满足研究需要。以可生物降解载体—乙交酯-丙交酯-己内酯三元共聚物为缓释辅料制备的环孢素A释药系统植入到兔葡萄膜炎动物模型眼玻璃体腔,前三个月间隔一周随机采集玻璃体标本,其后间隔两周至一个月随机采集玻璃体标本,连续采集八个月;测定环孢素A药物浓度,描绘浓度—时间曲线,并对该释药系统的药代动力学特征进行了初步评价。 论文全方位优化条件,获得了高灵敏度的色谱条件和生物标本前处理方法,首次将生物降解载体制备的环孢素A缓释系统植入到兔葡萄膜炎模型眼玻璃体腔,并对其药代动力学性能进行了初步评价,为环孢素A释药系统的开发与应用奠定了理论基础。更多还原

【Abstract】 Cyclosporine A is a selective immunosuppressant of neutral cyclohendecapeptide separated from fungal fermentation. Since clinical application started in 1978, this agent is now widely used in homotransplantations and immunotherapy.Uveitis probably causes damages to uvea, retina and vitreous body, and it is mostly related to immunological factors. Evidence acquired from experimental and clinical researches has indicated that Cyclosporine A can affect uveitis positively.Rabbit model of panuveitis is established by subcutaneous immunization and intravitreal injection successively with 10mg and 25μg Mycobacterium Tuberculosis H37Ra antigen respectively. Rechallenge with the same amount of antigen is performed intravitreally to those rabbits to simulate the recurrence of uveitis. As reference method, the traditional method of HPLC which is already widely used in therapeutic drug monitoring has the LOQ of 50ng/ml from 2ml whole blood. Thus it can not be used for measurement of small-volume samples with low concentration of CsA. Many procedures are optimized to enhance the detection sensitivity with good results which canmeet the requirement of current research. Cyclosporine A Drug Delivery System (CsA DDS) which is carried by biodegradable PGLC is implanted intravitreally in models and vitreous samples are extracted weekly for 3 months , biweekly for another 3 months and once for another two months. The concentration of CsA is measured and the concentration-time curve is drawn, which are analyzed and evaluated.In this paper, biodegradable CsA DDS is implanted intravitreal1y on rabbit model uveitis established with Mycobacterium Tuberculosis H37Ra as antigen, intravitreal concentration of CsA is measured by a more sensitive HPLC method, and the pharmacoki net i c features of CsA DDS areevaluated.更多还原