tacrolimus and Corneal-Neovascularization

To investigate the effect of tacrolimus in alkali burn-induced corneal neovascularization (NV) and inflammation and to compare with anti-vascular endothelial growth factor (anti-VEGF).. After corneal alkali-burn, 84 Wistar rats were randomly divided into three groups and received either saline solution or 0.05% tacrolimus (0.5 mg/mL) four times daily, or subconjunctival anti-VEGF injection (0.5 mg/0.05 mL). Corneal NV, opacity and epithelial defects, the status of inflammation, and the levels of proinflammatory and angiogenic cytokines were assessed on Days 3, 7, 14 and 28 post-injury.. Compared with the control, tacrolimus significantly reduced corneal NV on Days 7, 14 and 28 post-injury, and anti-VEGF significantly reduced corneal NV at each assessment. Nevertheless, the tacrolimus group had significantly less corneal NV than the anti-VEGF group on Days 14 and 28. Furthermore, both tacrolimus and anti-VEGF significantly decreased the VEGF-A expression on Days 7 and 14, with no significant difference between the two groups. Moreover, corneal inflammatory response was alleviated, and corneal opacity and epithelial defects were significantly reduced by tacrolimus. Additionally, the expression of IL-1β, IL-6, monocyte chemotactic protein-1, macrophage inflammatory protein-1α and TGF-β were significantly decreased by tacrolimus.. Our findings suggested that 0.05% tacrolimus suspension eye drops effectively reduced alkali burn-induced corneal NV and inflammation, with a better effect than subconjunctival anti-VEGF injections on Days 14 and 28.

Topics: Alkalies; Animals; Burns, Chemical; Corneal Neovascularization; Disease Models, Animal; Inflammation; Neovascularization, Pathologic; Rats; Rats, Wistar; Tacrolimus; Vascular Endothelial Growth Factors

To compare the antiangiogenic effects of tacrolimus and bevacizumab on corneal neovascularization (CNV) in rabbits.. Neovascularization was induced in 32 eyes of 16 rabbits by placing a suture in the corneal stroma. Seven days after suture placement, all rabbits were divided into 4 groups and were treated subconjunctivally with bevacizumab (AVA_sub) 0.05 mL (5 mg/0.05 mL), tacrolimus (TAC_sub) 0.05 mL (0.25 mg/0.05 mL), balanced salt solution (0.05 mL was subconjunctivally injected in 1 eye of each rabbit and applied by eye drops in the other eyes, control group), and tacrolimus eye drops (TAC_drop) (5 mg/5 mL applied 4 times daily). Digital photographs were obtained and surface area of CNV was measured 7 days after subconjunctival injections. Corneal specimens were analyzed histopathologically and were used to measure the concentration of vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin-1 beta (IL-1β), and monocyte chemoattractant protein 1 mRNA by reverse transcription polymerase chain reaction.. In digital photographs, the neovascularized area was decreased in all treatment groups (AVA_sub, 0.58; TAC_sub, 0.60; TAC_drop, 0.68) compared with the control group (balanced salt solution, 0.81). Histological examination showed markedly regressed new vessels in treatment groups, and immunohistochemical staining revealed weakly stained anti-VEGF and anti-F4/80 antibodies in treatment groups. In semiquantitative reverse transcription polymerase chain reaction, concentration of VEGF (AVA_sub, 0.24; TAC_drop, 0.18), TNF-α (AVA_sub, 0.19; TAC_sub, 0.24; TAC_drop 0.15), and IL-1β (AVA_sub, 0.19; TAC_sub, 0.33; TAC_drop, 0.18) mRNA were significantly lower in treatment groups than in the control group (VEGF, 0.47; TNF-α, 0.44; IL-1β, 0.87) (P < 0.05).. Topical and subconjunctival tacrolimus application may be useful in reducing CNV and have comparable effects to subconjunctival bevacizumab injection.

Topics: Administration, Topical; Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal, Humanized; Bevacizumab; Chemokine CCL2; Conjunctiva; Corneal Neovascularization; Disease Models, Animal; Immunosuppressive Agents; Injections, Intraocular; Interferon-gamma; Interleukin-1beta; Ophthalmic Solutions; Rabbits; Real-Time Polymerase Chain Reaction; RNA, Messenger; Tacrolimus; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

To report 2 cases of refractory phlyctenular keratoconjunctivitis treated with topical tacrolimus 0.03% ointment (Protopic).. Two white children, aged 5 years and 6 years, respectively, presented with refractory phlyctenular keratoconjunctivitis in 1 eye (left). Both were using corticosteroids and oral erythromycin at presentation with no relief. Examination revealed the presence of catarrhal corneal infiltrates and neovascularization associated with corneal thinning. Topical tacrolimus was added to topical steroids and oral erythromycin twice daily.. Topical tacrolimus 0.03% ointment was applied into the lower fornix twice a day. In both the patients, improvement in symptoms and signs started within a week of therapy. After 3 weeks of treatment, both patients showed complete resolution of corneal infiltrates and neovascularization. Tacrolimus was successfully tapered in both the patients. There were no side effects.. Topical tacrolimus 0.03% ointment may be considered in treating severe refractory phlyctenular conjunctivitis.

Topics: Child; Child, Preschool; Cornea; Corneal Neovascularization; Female; Humans; Immunosuppressive Agents; Keratoconjunctivitis; Ointments; Tacrolimus

To investigate the impact of tacrolimus on vascular endothelial growth factor (VEGF) in experimental corneal neovascularization (NV) immunohistochemically.. Five groups of seven Wistar albino rats were formed. A silver nitrate cauterization technique was used to induce corneal NV in the study groups, excluding Group 1 (Control Group). Rats in group 1 did not receive any treatment. Rats in group 2 (sham 1) were administered 1 ml of saline intraperitoneally once a day and those in group 3 (sham 2) received one drop of saline four times a day. Rats in group 4 were administered 0.3 mg/kg tacrolimus intraperitoneally once a day. For group 5, 0.3 mg/ml tacrolimus was installed four times a day. Digital photography for each cornea was performed and the percentage area of the NV on the total corneal surface was calculated. The intensity of VEGF immunostaining in the epithelial, the stromal, and endothelial layers was performed in a semi quantitative fashion.. The mean percentages of the neovascularized areas of intraperitoneally and topically tacrolimus-treated groups were lesser than those of the sham groups (p = 0.002, p = 0.038, respectively). The mean intensity of the epithelial VEGF immunostaining of the intraperitoneally tacrolimus-treated group was less than that of its sham group (p = 0.002), while the mean intensity of the stromal VEGF staining of the topically tacrolimus-treated group was lesser than that of its sham group (p = 0.042). The intensities of the endothelial VEGF immunostaining of the intraperitoneally and topically tacrolimus-treated groups were less than those of the sham groups (p = 0.038, p = 0.032).. Systemic and topical administration of tacrolimus may be beneficial in the prevention of corneal NV because of its effect on VEGF.

Topics: Administration, Topical; Animals; Corneal Neovascularization; Disease Models, Animal; Immunoenzyme Techniques; Immunosuppressive Agents; Injections, Intraperitoneal; Male; Rats; Rats, Wistar; Tacrolimus; Vascular Endothelial Growth Factor A

FK-506 is a relatively new immunosuppressant similar in action to cyclosporine A, but is much more potent. Its primary action is against T lymphocytes, the major cellular component in corneal allograft rejection. The purpose of this study was the evaluation of the ability of topical and systemic FK-506 in preventing corneal xenograft rejection in an experimental animal model. Cross-species xenotransplants were used as the most vigorous stimulus to induce corneal rejection. Corneas derived from Hartley guinea pigs were transplanted into the left eyes of 32 male Lewis rats. Topical treatment was administered by using FK-506 0.3 mg/ml in a cyclodextrin suspension or vehicle (cyclodextrin suspension) four times per day. For systemic treatment, 0.5 mg/kg/day of FK-506 or vehicle (saline) was administered intraperitoneally. Treatments were started 60 minutes after surgery and continued for 21 days. The grafts underwent a double-masked examination, and a score was given for clarity, edema, and vascularization. The animals were sacrificed 21 days after transplantation. The control groups had allograft rejection after 6.75 +/- 0.31 (topical vehicle) and after 7.37 +/- 0.32 (systemic vehicle) days. The FK-506-treated groups showed allograft rejection after 14 +/- 0.88 (topical FK-506) or after 16.25 +/- 1.23 (systemic FK-506) days. In addition, FK-506-treated rats manifested less corneal neovascularization than control animals. We conclude that systemic or topical FK-506 is effective in prolonging xenograft survival in the rat keratoplasty model.

Topics: Administration, Topical; Animals; Cornea; Corneal Neovascularization; Corneal Transplantation; Disease Models, Animal; Double-Blind Method; Graft Rejection; Graft Survival; Guinea Pigs; Immunosuppressive Agents; Injections, Intraperitoneal; Male; Ophthalmic Solutions; Rats; Rats, Inbred Lew; Tacrolimus; Transplantation, Heterologous

We evaluated the efficacy of topical cyclodextrin-encapsulated FK-506 in the prevention of experimental corneal allograft rejection. Two weeks after inducing corneal inflammation and neovascularization with 8-0 silk sutures, 23 albino rabbits received a unilateral 8-mm diameter central penetrating corneal allograft from pigmented donors. Rabbits were randomly assigned to no treatment (eight eyes), topical cyclodextrin four times daily for 28 days (seven eyes), or topical FK-506 0.3 mg/ml in a cyclodextrin suspension (eight eyes) four times daily for 28 days. Grafts were examined daily for degree of inflammation, neovascularization, edema, and signs of rejection for up to 100 days. Seven of eight (88%) untreated grafts and five of seven (71%) cyclodextrin-treated grafts rejected at a median of 3 weeks after transplantation, whereas only two (25%) of eight FK-506-treated grafts rejected and did so at a significantly longer interval (p < 0.005). Topical FK-506 prevents or delays corneal allograft rejection after experimental corneal transplantation.

Topics: Administration, Topical; Animals; Corneal Neovascularization; Cyclodextrins; Disease Models, Animal; Drug Carriers; Graft Rejection; Graft Survival; Keratitis; Keratoplasty, Penetrating; Ophthalmic Solutions; Rabbits; Random Allocation; Tacrolimus; Transplantation, Homologous