Suppressive effects of selectin inhibitor SKK-60060 on the leucocyte infiltration during endotoxin induced uveitis.

BACKGROUND: It is well known that selectin is involved in the development of endotoxin induced uveitis (EIU), and has a major role in leucocyte infiltration. Recently, a novel selectin inhibitor (SKK-60060) that can block P and L selectins in vitro has been developed. This study was designed to investigate the anti-inflammatory effects of SKK-60060 on the inflammatory reaction during EIU in rats by studying leucocyte-endothelium interactions. METHODS: EIU was induced in Lewis rats by footpad injection of lipopolysaccharide (LPS). SKK-60060 was administered 15 minutes before LPS injection, and its suppressive effects on inflammatory leucocyte behaviour were evaluated in vivo with acridine orange digital fluorography; the diameters of retinal arteries and veins were also measured. After these studies, aqueous humour was collected to evaluate leucocyte infiltration and protein leakage. RESULTS: After LPS injection, rolling leucocytes were observed in major retinal veins, followed by leucocyte infiltration into the vitreous cavity. Following treatment with SKK-60060, leucocyte rolling was significantly inhibited in the retinal veins (p <0.01), and subsequent leucocyte infiltration into the vitreous cavity was also significantly suppressed (p <0.01). Retinal vasodilation was also substantially suppressed in SKK-60060 treated rats (p <0.01). Similarly, leucocyte infiltration and protein leakage into the aqueous humour were reduced significantly by SKK-60060 (p <0.01). CONCLUSIONS: SKK-60060 treatment significantly inhibited the inflammatory reaction induced by LPS. Its inhibitory effects on P and L-selectin resulted in suppression of leucocyte infiltration and the subsequent inflammatory reaction caused by accumulated leucocytes. The current findings suggest that SKK-60060 may be useful in the management of uveitis.

Monoclonal antibody-mediated drug targeting to choroidal neovascularization in the rat.

PURPOSE: Active drug targeting mediated by monoclonal antibodies (mAbs) of vascular endothelial cells in tumors is a new concept in cancer therapy. Integrin alphavbeta3 has been reported to be strongly expressed in vascular endothelial cells of surgically excised choroidal neovascular membranes and is thought to be a potential antigen for mAb-mediated drug targeting of choroidal neovascularization (CNV). The objective of this study was to evaluate the efficacy of drug targeting mediated by anti-integrin alphavbeta3 mAbs in a laser-induced CNV rat model. METHODS: The mitomycin C (MMC)-dextran (MMCD) conjugate was synthesized with a carbodiimide-catalyzed reaction. The mAb was conjugated with MMCD (MMCD-mAb). To evaluate the feasibility of mAb-mediated drug targeting in vitro, we investigated the effect of the immunoconjugates involving dextran-binding MMC on the proliferation of human umbilical vein endothelial cells (HUVECs). CNV was induced by laser photocoagulation in male Brown Norway rats. Immunolocalization of integrin alphavbeta3 in CNV lesions was assessed immunohistochemically with the anti-von Willebrand factor antibody as an endothelial cell marker. Intravenous administration of saline (n = 7), 1 mg/day mAb (n = 7), 100 microg/kg per day free MMC (n = 7), MMCD with irrelevant Ab (n = 7), unconjugated MMCD with unconjugated mAb (MMCD+mAb; n = 7), or MMCD with mAb (MMCD-mAb; n = 8) containing an equal amount of free MMC, was performed daily for 3 days from day 14 after CNV induction. CNV was assessed by fluorescein angiography 2 weeks after treatment. Fluorescein leakage was scored on a four-grade scale. The animals were killed 2 weeks after treatment, and the lesions were evaluated histologically. RESULTS: The inhibition of immunoconjugates on the proliferation of HUVECs was enhanced specifically by the mediatory effect of the mAb. Endothelial cells demonstrated strong immunoreactivity of integrin alphavbeta3 in the CNV. In the vehicle-treated group, fluorescein leakage equal to that before treatment was observed 2 weeks after treatment, with an average score of 2.00 +/- 0.17 (mean +/- SEM). MMCD-mAb significantly inhibited the development of CNV in rats (P < 0.01). Moreover, the thickness of the lesions was significantly reduced in the MMCD-mAb-treated group (P < 0.01). CONCLUSIONS: Immunoconjugates effectively inhibited progression of CNV in this model. The results suggest that mAb-mediated drug targeting may be beneficial in the treatment of CNV.

[A case of bilateral continuous central retinal artery occlusion].

BACKGROUND: We report a case of bilateral simultaneous central retinal artery occlusion (CRAO). The time lag was 21 hours. CASE: The patient was a 78-year-old woman. She had hypertension, arteriosclerosis, and bilateral thrombosis of the legs. Both eyes could only distinguish light and dark at the first medical examination. RESULTS: We started steroid and urokinase therapy and used a vasodilator of peripheral vessels. When the patient left the hospital, visual acuity had improved to the ability of counting fingers (0.01 leftward 30 cm on the left). CONCLUSIONS: Both visual field and color vision had improved slightly. We think this bilateral CRAO resulted from thrombosis of both central retinal arteries at almost the same time.