Aguirre Shirley A, Collette Walter, Gukasyan Hovhannes J, Huang Wenhu
Drug Safety Research and Development, La Jolla Laboratories, Pfizer Inc., San Diego, California, USA.
Toxicol Pathol. 2012 Jul;40(5):797-806. doi: 10.1177/0192623312441400. Epub 2012 May 2.
Maleic acid was formulated in 0.7% saline and injected intravitreally in rabbits in order to evaluate ocular safety and tolerability. Maleic acid was formulated within a narrow pH range (2-3), administered in a fixed volume (100 µl), and concentrations ranged from 0.00 to 2.00 mg/eye (0.00 to 12.30 mM vitreous). Ocular evaluations were conducted at 2, 4, and 8 days post injection. Ocular irritation responses were observed at doses from 0.50 mg/eye (3.07 mM vitreous) to 2.00 mg/eye (12.30 mM vitreous) and included conjunctival redness and scleral swelling. Chemosis was observed at 2.00 mg/eye (12.30 mM vitreous). Funduscopic evaluations revealed enlarged retinal blood vessels and optic disk swelling at doses ≥1.50 mg/eye (9.22 mM vitreous), retinal folds and retinal discoloration at 2.00 mg/eye (12.30 mM vitreous). Histopathologic evaluations on days 4 and 8 post injection revealed retinal degeneration at doses ≥1.0 mg/eye (6.15 mM vitreous), conjunctival inflammation at doses ≥1.5 mg/eye (9.22 mM vitreous), and retinal pigment epithelial hypertrophy, optic nerve demyelination, anterior chamber fluid, and conjunctival fibrosis at 2.00 mg/eye (12.30 mM vitreous) maleic acid. The data suggest that maleic acid formulations at ≥1.00 mg/eye (6.15 mM vitreous) were not suitable for intraocular indications.
将马来酸配制成0.7%的盐水溶液，并对兔子进行玻璃体内注射，以评估眼部安全性和耐受性。马来酸在较窄的pH范围（2-3）内配制，以固定体积（100 μl）给药，浓度范围为0.00至2.00 mg/眼（玻璃体内0.00至12.30 mM）。在注射后第2、4和8天进行眼部评估。在0.50 mg/眼（玻璃体内3.07 mM）至2.00 mg/眼（玻璃体内12.30 mM）的剂量下观察到眼部刺激反应，包括结膜充血和巩膜肿胀。在2.00 mg/眼（玻璃体内12.30 mM）时观察到球结膜水肿。眼底评估显示，剂量≥1.50 mg/眼（玻璃体内9.22 mM）时视网膜血管扩张和视盘肿胀，2.00 mg/眼（玻璃体内12.30 mM）时出现视网膜褶皱和视网膜变色。注射后第4天和第8天的组织病理学评估显示，剂量≥1.0 mg/眼（玻璃体内6.15 mM）时出现视网膜变性，剂量≥1.5 mg/眼（玻璃体内9.22 mM）时出现结膜炎症，2.00 mg/眼（玻璃体内12.30 mM）的马来酸导致视网膜色素上皮肥大、视神经脱髓鞘、前房积液和结膜纤维化。数据表明，≥1.00 mg/眼（玻璃体内6.15 mM）的马来酸制剂不适用于眼内给药。
