Dataset Information

The Effect of CM082, an Oral Tyrosine Kinase Inhibitor, on Experimental Choroidal Neovascularization in Rats.

ABSTRACT: The aims of this study were to evaluate the effects of CM082 on the development of choroidal neovascularization (CNV) in a laser-induced CNV rat model and to determine the drug concentration in the ocular tissues. After the laser-induced CNV model was established in rats, CM082 was orally administered. The effects of CM082 on the CNV lesions were assessed using fundus fluorescein angiography (FFA), CNV histology, and retinal pigment epithelium- (RPE-) choroid-sclera eyecup analysis. The concentrations of CM082 in the plasma and eye tissues were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results of FFA, histology, and RPE-choroid-sclera eyecup analysis demonstrated that the CM082-treated (10?mg/kg/d or 30?mg/kg/d) rats exhibited significantly less neovascularization than did the control group. The total concentration of CM082 in the eyes (172.86?±?57.11?ng/g) was similar to that in the plasma (196.87?±?73.13?ng/ml). Within the eye, the concentrations of CM082 and its metabolites were highest in the retina-sclera. The orally administered CM082 thus effectively passed through the blood-retina barrier (BRB) to reach the retina in the Brown Norway rats. Therefore, at both 10?mg/kg/d and 30?mg/kg/d, CM082 was able to reduce CNV lesions in the laser-induced CNV rat model.

SUBMITTER: Ren C

PROVIDER: S-EPMC5671735 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The Effect of CM082, an Oral Tyrosine Kinase Inhibitor, on Experimental Choroidal Neovascularization in Rats.

Ren Chengda C Shi Hui H Jiang Juanjuan J Liu Qingyu Q Du Yaru Y He Mengmei M Cai Wenting W Wei Qingquan Q Yu Jing J

Journal of ophthalmology 20171022

The aims of this study were to evaluate the effects of CM082 on the development of choroidal neovascularization (CNV) in a laser-induced CNV rat model and to determine the drug concentration in the ocular tissues. After the laser-induced CNV model was established in rats, CM082 was orally administered. The effects of CM082 on the CNV lesions were assessed using fundus fluorescein angiography (FFA), CNV histology, and retinal pigment epithelium- (RPE-) choroid-sclera eyecup analysis. The concentr ...[more]

PMID: 29201457

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Project description:Choroidal neovascularization (CNV) is a major cause of severe visual loss in patients with age-related macular degeneration (AMD). Recently, itraconazole has shown potent and dose-dependent inhibition of tumor-associated angiogenesis. We evaluated the anti-angiogenic effect of itraconazole in a rat model of laser-induced CNV. After laser photocoagulation in each eye to cause CNV, right eyes were administered intravitreal injections of itraconazole; left eyes received balanced salt solution (BSS) as controls. On day 14 after laser induction, fluorescein angiography (FA) was used to assess abnormal vascular leakage. Flattened retinal pigment epithelium (RPE)-choroid tissue complex was stained with Alexa Fluor 594-conjugated isolectin B4 to measure the CNV area and volume. Vascular endothelial growth factor receptor 2 (VEGFR2) mRNA and protein expression was determined 1, 4, 7, and 14 days after intravitreal injection by quantitative RT-PCR or Western blot. VEGF levels were analyzed by enzyme-linked immunosorbent assay (ELISA). Intravitreal itraconazole significantly reduced leakage from CNV as assessed by FA and CNV area and volume on flat mounts compared with intravitreal BSS (p = 0.002 for CNV leakage, p<0.001 for CNV area and volume). Quantitative RT-PCR showed significantly lower expression of VEGFR2 mRNA in the RPE-choroid complexes of itraconazole-injected eyes than those of BSS-injected eyes on days 7 and 14 (p = 0.003 and p = 0.006). Western blots indicated that VEGFR2 was downregulated after itraconazole treatment. ELISA showed a significant difference in VEGF level between itraconazole-injected and BSS-injected eyes on days 7 and 14 (p = 0.04 and p = 0.001). Our study demonstrated that intravitreal itraconazole significantly inhibited the development of laser-induced CNV in rats. Itraconazole had anti-angiogenic activity along with the reduction of VEGFR2 and VEGF levels. Itraconazole may prove beneficial for treating CNV as an alternative or adjunct to other therapies.

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Dataset Information

The Effect of CM082, an Oral Tyrosine Kinase Inhibitor, on Experimental Choroidal Neovascularization in Rats.

Publications

The Effect of CM082, an Oral Tyrosine Kinase Inhibitor, on Experimental Choroidal Neovascularization in Rats.

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