局部用奈帕芬胺可抑制眼部新生血管形成。

Topical nepafenac inhibits ocular neovascularization.

作者信息

Takahashi Kyoichi, Saishin Yoshitsugu, Saishin Yumiko, Mori Keisuke, Ando Akira, Yamamoto Satoru, Oshima Yuji, Nambu Hiroyuki, Melia Michele B, Bingaman David P, Campochiaro Peter A

机构信息

Departments of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287-9277, USA.

出版信息

Invest Ophthalmol Vis Sci. 2003 Jan;44(1):409-15. doi: 10.1167/iovs.02-0346.

DOI:10.1167/iovs.02-0346

PMID:12506103

Abstract

PURPOSE

Topical nepafenac readily penetrates the cornea and is metabolized to amfenac, a potent cyclooxygenase (COX)-1 and COX-2 inhibitor. In this study, we tested the effect of topical nepafenac in three murine models of ocular neovascularization (NV).

METHODS

A masked trial was performed to compare the topical effects of vehicle with one of several concentrations of nepafenac (0.01%, 0.03%, 0.1%, or 0.5%), 0.1% diclofenac, or 0.5% ketorolac tromethamine in mice with oxygen-induced ischemic retinopathy, mice with choroidal NV (CNV) due to laser-induced rupture of Bruch's membrane, or transgenic mice with increased expression of vascular endothelial growth factor (VEGF) in photoreceptors (rho/VEGF transgenic mice).

RESULTS

Mice treated with 0.1% or 0.5% nepafenac had significantly less CNV and significant less ischemia-induced retinal NV than did vehicle-treated mice. Nepafenac also blunted the increase in VEGF mRNA in the retina induced by ischemia. In rho/VEGF transgenic mice, nepafenac failed to inhibit neovascularization. In additional studies, compared with vehicle-treated mice, mice treated with 0.1% or 0.03% nepafenac had significantly less CNV, whereas eyes treated with 0.1% diclofenac showed no significant difference. Mice treated with 0.5% ketorolac tromethamine for 14 days had high mortality, but when evaluated after 7 days of treatment showed no difference from mice treated with vehicle for 7 days.

CONCLUSIONS

Topical nepafenac inhibits CNV and ischemia-induced retinal neovascularization by decreasing production of VEGF. The absence of effect in rho/VEGF transgenic mice is consistent with this mechanism. Topical nepafenac may provide an effective new treatment for ocular neovascularization. The excellent corneal penetration of nepafenac certainly plays an important role in this effect. It is possible that other antiangiogenic agents are also amenable to topical application after formulations are identified that maximize their corneal penetration. Because of the many advantages of the topical route of delivery, this is a possible topic for exploration.

摘要

目的

局部应用萘非那酸可轻易穿透角膜并代谢为氨苯酰酸，一种强效的环氧化酶（COX）-1和COX-2抑制剂。在本研究中，我们测试了局部应用萘非那酸在三种眼部新生血管（NV）小鼠模型中的作用。

方法

进行了一项盲法试验，比较赋形剂与几种浓度（0.01%、0.03%、0.1%或0.5%）的萘非那酸、0.1%双氯芬酸或0.5%酮咯酸氨丁三醇对氧诱导的缺血性视网膜病变小鼠、激光诱导布鲁赫膜破裂所致脉络膜新生血管（CNV）小鼠或光感受器中血管内皮生长因子（VEGF）表达增加的转基因小鼠（rho/VEGF转基因小鼠）的局部作用。

结果

用0.1%或0.5%萘非那酸处理的小鼠，其CNV和缺血诱导的视网膜NV明显少于赋形剂处理的小鼠。萘非那酸还减弱了缺血诱导的视网膜中VEGF mRNA的增加。在rho/VEGF转基因小鼠中，萘非那酸未能抑制新生血管形成。在其他研究中，与赋形剂处理的小鼠相比，用0.1%或0.03%萘非那酸处理的小鼠CNV明显较少，而用0.1%双氯芬酸处理的眼睛无明显差异。用0.5%酮咯酸氨丁三醇处理14天的小鼠死亡率很高，但在处理7天后评估时，与用赋形剂处理7天的小鼠无差异。

结论

局部应用萘非那酸通过减少VEGF的产生来抑制CNV和缺血诱导的视网膜新生血管形成。在rho/VEGF转基因小鼠中无作用与该机制一致。局部应用萘非那酸可能为眼部新生血管形成提供一种有效的新治疗方法。萘非那酸出色的角膜穿透性在这种作用中肯定起着重要作用。在确定能最大化其角膜穿透性的制剂后，其他抗血管生成药物也可能适合局部应用。由于局部给药途径有许多优点，这是一个可能值得探索的课题。