局部用环孢素A前药对大鼠角膜移植排斥反应的评估。

Evaluation of a topical cyclosporine A prodrug on corneal graft rejection in rats.

作者信息

Bourges J L, Lallemand F, Agla E, Besseghir K, Dumont J M, BenEzra D, Gurny R, Behar-Cohen F

机构信息

INSERM, U598, Paris, France.

出版信息

Mol Vis. 2006 Dec 2;12:1461-6.

PMID:17167400

Abstract

PURPOSE

To assess the efficacy of a topical cyclosporine A (CsA), water-soluble prodrug, for promoting the survival of allogenic rat corneal grafts after penetrating keratoplasty (PKP).

METHODS

Corneas of Brown-Norway rats (donors) were transplanted to Lewis rats (recipients). Transplanted rats were divided in three treatment groups: group I (PBS) and group II (0.26% Debio088) received drops five times per day. Group III received a daily intramuscular CsA injection (10 mg/kg/day). Blood CsA concentrations were measured on days 2 and 14. On day 4, 10, 13 after PKP, grafts were scored for corneal transparency, edema and extent of neovascularization. An opacity score of greater than or equal to 3 was considered as a nonreversible graft rejection process. On day 14, the experimental eyes were processed for histology.

RESULTS

On day 13, 12 of the 18 corneal transplants (67%) in group I showed irreversible graft rejection. Three of 18 transplants (19%) in group II and 5 of 16 transplants (28%) in group III showed irreversible graft rejection (p=0.013/p=0.019, OR=0.14/0.06 versus vehicle). Each mean clinical score for edema, opacity, and neovessels in group II were significantly lower than those of the grafts in group I (respectively p=0.010, p=0.013, p=0.024) and III except for neovessels (respectively p=0.002, p=0.001, p=0.057). Histology confirmed the clinical results. The mean CsA blood levels for groups II and III were, respectively 54+/-141 mug/l and 755+/-319 mug/l on day 2 and 14+/-34 mug/l and 1318+/-463 mug/l on day 14.

CONCLUSIONS

Debio088 CsA prodrug drops given five times daily are as effective as intramuscular injection of 10 mg/kg/day for the prevention of acute corneal graft rejection in rats.

摘要

目的

评估局部应用环孢素A（CsA）水溶性前药对穿透性角膜移植术（PKP）后同种异体大鼠角膜移植片存活的促进作用。

方法

将棕色挪威大鼠（供体）的角膜移植到刘易斯大鼠（受体）。移植后的大鼠分为三个治疗组：I组（PBS）和II组（0.26% Debio088）每天滴眼5次。III组每天肌肉注射CsA（10 mg/kg/天）。在第2天和第14天测量血CsA浓度。在PKP后的第4、10、13天，对移植片的角膜透明度、水肿和新生血管程度进行评分。不透明度评分大于或等于3被认为是不可逆的移植排斥过程。在第14天，对实验眼进行组织学检查。

结果

在第13天，I组18只角膜移植片中的12只（67%）出现不可逆的移植排斥。II组18只移植片中的3只（19%）和III组16只移植片中的5只（28%）出现不可逆的移植排斥（p = 0.013/p = 0.019，与赋形剂相比，OR = 0.14/0.06）。II组中水肿、不透明度和新生血管的每项平均临床评分均显著低于I组（分别为p = 0.010、p = 0.013、p = 0.024）和III组中移植片的评分，但新生血管除外（分别为p = 0.002、p = 0.001、p = 0.057）。组织学检查证实了临床结果。II组和III组在第2天的平均CsA血药浓度分别为54±141 μg/l和755±319 μg/l，在第14天分别为14±34 μg/l和1318±463 μg/l。