Evaluation of a topical cyclosporine A prodrug on corneal graftrejection in rats

[摘要] Purpose: To assess the efficacy of a topical cyclosporine A (CsA),water-soluble prodrug, for promoting the survival of allogenic ratcorneal grafts after penetrating keratoplasty (PKP).Methods: Corneas of Brown-Norway rats (donors) were transplanted toLewis rats (recipients). Transplanted rats were divided in threetreatment groups: group I (PBS) and group II (0.26% Debio088) receiveddrops five times per day. Group III received a daily intramuscular CsAinjection (10 mg/kg/day). Blood CsA concentrations were measured on days2 and 14. On day 4, 10, 13 after PKP, grafts were scored for cornealtransparency, edema and extent of neovascularization. An opacity scoreof greater than or equal to 3 was considered as a nonreversible graftrejection process. On day 14, the experimental eyes were processed forhistology.Results: On day 13, 12 of the 18 corneal transplants (67%) in groupI showed irreversible graft rejection. Three of 18 transplants (19%) ingroup II and 5 of 16 transplants (28%) in group III showed irreversiblegraft rejection (p=0.013/p=0.019, OR=0.14/0.06 versus vehicle). Eachmean clinical score for edema, opacity, and neovessels in group II weresignificantly lower than those of the grafts in group I (respectivelyp=0.010, p=0.013, p=0.024) and III except for neovessels (respectivelyp=0.002, p=0.001, p=0.057). Histology confirmed the clinical results.The mean CsA blood levels for groups II and III were, respectively54±141 μg/l and 755±319 μg/l on day 2 and 14±34 μg/l and 1318±463 μg/l on day 14.Conclusions: Debio088 CsA prodrug drops given five times daily areas effective as intramuscular injection of 10 mg/kg/day for theprevention of acute corneal graft rejection in rats.

[学科分类] 生物化学/生物物理