Preliminary Study of the Effect of FK506 Nanospheric-Suspension Eye Drops on Rejection of Penetrating Keratoplasty

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China.
Journal of Ocular Pharmacology and Therapeutics (Impact Factor: 1.47). 05/2008; 24(2):235-44. DOI: 10.1089/jop.2007.0059
Source: PubMed


The aim of this study was to investigate the effect of a topical FK506 nanospheric suspension in a rat model of penetrating keratoplasty.
FK506 nanospheres were prepared by using a biodegradable poly (lactic-co-glycolic acid) copolymer (PLGA). Its distribution in the eye and blood after a single instillation was examined in rabbits. Sprague-Dawley (SD) rats received corneal heterografts and were topically treated with phosphate-buffered saline (PBS), PLGA, FK-506 0.01% (nanospheres), or dexamethasone 0.05% solutions twice a day for 28 days. Rejection index and graft-survival time were recorded and compared between the four groups. Three grafts were collected at different time points for immunohistochemical studies.
In the cornea, the FK-506 concentration reached its peak within 1 h of a single eye-drop instillation and then decreased by half (1667.85 +/- 611.87 ng/g) at 8 h. FK-506 cannot be detected in rabbit blood. There were significant differences in the graft-survival time between the FK-506 nanosphere group (15.09 +/- 4.81 days) and the other three groups [PBS (7.90 +/- 1.20, t = -4.594, P < 0.001), PLGA (8.44 +/- 0.88, t = - 4.074, P = 0.001) and dexamethasone (10.44 +/- 1.42, t = -2.790, P = 0.012)]. The rejected corneas in the FK506 nanosphere group showed significantly fewer CD4, CD8, CD68, CD79, vascular endothelial growth factor, ICAM, and tumor growth factor-beta(1)-positive cells than those in the other groups.
FK506 0.01% nanospheric-suspension eye drops delayed the occurrence of corneal allograft rejection and prolonged allograft survival time. The FK506 nanospheres may be valuable in suppressing corneal graft rejection.

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    • "Tacrolimus is a macrolide with immunomodulatory action that was isolated from Streptomyces tsukubaensis fermentation and becomes biologically active only when it binds to immunophilin. Tacrolimus (FK506) inhibits calcium-dependent events, such as interleukin-2 gene transcription , nitric oxide synthase activation, cell degranulation, and apoptosis [6] [7] [8] [9] [10] [11] [12]. Generally, tacrolimus suppresses the immune "
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    • "In the current study, we investigated the immunosuppressive effect of FK506 on preventing the development of epidural scar adhesion. The concentration of FK506 chosen was based on previous research (Fei et al., 2008; Arslan et al., 2012). Multiple parameters including the Rydell classification, the hydroxyproline content, the histological analysis, the number of fibroblasts and the mRNA measurement were used to evaluate the effect of FK506 on preventing epidural adhesion after laminectomy. "
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    ABSTRACT: There was no previous study about topical application of tacrolimus (FK506) could inhibit fibroblast proliferation and prevent epidural scar adhesion after laminectomy. We intended to illustrate the effect of FK506 on inhibiting fibroblast proliferation and preventing epidural scar adhesion after laminectomy in rat model. In our study, seventy-two rats were randomly divided into four groups (0.1mg/ml group, 0.05mg/ml group, 0.01mg/ml group and control group). Laminectomy was performed at Lumbar-1 level, and then different concentrations of FK506 and saline were applied to the laminectomy sites. Four weeks later the rats were killed and the epidural adhesion was evaluated. Macroscopic assessment, hydroxyproline content analysis, histological analysis and mRNA measurements were used to evaluate the effect of FK506 on reducing epidural scar adhesion. The results showed that FK506 could prevent epidural scar adhesion in a dose-dependent manner. Little epidural adhesions were seen in the laminectomy sites treated with 0.1mg/ml FK506. The hydroxyproline content, the number of fibroblasts, the mRNA expression level of IL-2 and TGF-β1 in 0.1mg/ml FK506 group were significantly less than those of 0.05mg/ml FK506 group, 0.01mg/ml FK506 group and control group. However, dense epidural adhesions were found in 0.01mg/ml FK506 group and control group. The hydroxyproline content and the number of fibroblasts in 0.01mg/ml group showed no significant difference compared with those of control group. In conclusion, topical application of 0.1mg/ml FK506 could inhibit fibroblast proliferation and prevent epidural scar adhesion after laminectomy in rat model.
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