Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR).
Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR).
复制标题
通过滴眼剂将 SAR 1118 递送至视网膜及其在糖尿病视网膜病变 (DR) 大鼠链脲佐菌素 (STZ) 模型中的有效性。
DOI：
10.1167/iovs.09-5144
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发表时间：
2010
影响因子：
4.4
通讯作者：
Kompella,UdayB
中科院分区：
文献类型：
--
作者：
Rao,VidhyaR;Prescott,Elizabeth;Shelke,NamdevB;Trivedi,Ruchit;Thomas,Peter;Struble,Craig;Gadek,Tom;O'Neill,CharlesA;Kompella,UdayB
Purpose.: To determine the pharmacokinetics of SAR 1118, a small-molecule antagonist of leukocyte function-associated antigen (LFA)-1, after administration of ophthalmic drops in normal rats, and to determine its pharmacologic activity by assessing the inhibition of retinal leukostasis and vascular leakiness in a streptozotocin (STZ)-induced diabetic retinopathy model.Methods.: The ocular pharmacokinetics of SAR 1118 were studied in rats after a single topical dose of 14 C-SAR 1118 (1 mg/eye; 40 μCi; 15.5 μL). SAR 1118 concentration time profiles in plasma and ocular tissues were quantified by liquid scintillation counting (LSC). The pharmacologic activity of SAR 1118 eye drops administered thrice daily for 2 months at 1%(0.3 mg/eye/d) and 5%(1.5 mg/eye/d) was assessed in an STZ-induced diabetic rat model by determining retinal leukostasis and blood–retinal barrier breakdown. Diabetic rats treated with periocularly administered celecoxib microparticles served as the positive control, and vehicle-treated rats served as the negative control.Results.: A single dose of 6.5% 14 C-radiolabeled SAR 1118 ophthalmic drops delivered retinal drug levels greater than 1 μM in less than 30 minutes and sustained levels greater than 100 nM for 8 hours. SAR 1118 eye drops significantly reduced leukostasis and blood–retinal barrier breakdown in a dose-dependent manner.Conclusions.: SAR 1118 ophthalmic drops administered thrice daily deliver therapeutic levels of SAR 1118 in the retina and can alleviate the retinal complications associated with diabetes.
