anecortave and Disease-Models--Animal

To determine the effect of triamcinolone acetonide (TA) on outflow facility in mice.. Animals received 20 μL of TA (40 mg/mL) suspension subconjunctivally either bilaterally or unilaterally and were euthanized after either 1 week or 3 weeks. Before mice were killed, IOP was measured with a rebound tonometer. Outflow facility was determined using simultaneous pressure and flow measurements. Another set of animals received bilateral injection of anecortave acetate (AA) with or without bilateral TA injection and their outflow facility was also determined. Myocilin expression was investigated in a subset of eyes using quantitative PCR (qPCR).. Outflow facility of eyes in animals receiving bilateral TA injection (TA(BL)) and TA-treated eyes of animals receiving unilateral injection (TA(UL)) was significantly decreased compared to naïve control eyes (C(naive)) after 1 week and 3 weeks of TA treatment (ANOVA P < 0.01, P < 0.001, respectively). Eyes treated with AA (with or without TA) had higher outflow facility than animals treated with TA (P < 0.05). IOP data did not show any significant difference between groups. qPCR analysis revealed significant decrease in myocilin expression in eyes receiving AA compared to naïve control and TA-treated eyes (ANOVA P < 0.001).. Steroid treatment significantly decreases outflow facility in C57BL/6 mice despite having small effect on IOP. This animal model can be useful for studying the pathogenesis of steroid-induced glaucoma.

Topics: Animals; Cytoskeletal Proteins; Disease Models, Animal; Eye Proteins; Female; Glaucoma; Glucocorticoids; Glycoproteins; Hydrocortisone; Intraocular Pressure; Mice; Mice, Inbred C57BL; Microdialysis; Models, Biological; RNA, Messenger; Trabecular Meshwork; Triamcinolone Acetonide

Ocular neovascular diseases represent a major cause of blindness in the world. Angiostatic steroids are a unique class of compounds which inhibit the formation of new blood vessels in various models, including ocular models of angiogenesis. In search of potent new anti-angiogenic agents for the treatment of ocular neovascular disease, a large group of steroids were evaluated for angiostatic activity in the chick embryo CAM model. Angiostatic activity was found among all steroid classes included in the study. There was a good correlation between the angiostatic efficacies of 15 diverse steroids tested in the chick CAM and in the rabbit LPS-induced corneal pocket models of neovascularization (r=0.76, p=0.01). These studies show that potent angiostatic steroids inhibit neovascularization in two different animal models, suggesting a common mechanism of action. Glucocorticoid therapy is sometimes associated with ocular side effects. Two of the most potent angiostatic steroids, AL-3789 and AL-4940, were evaluated for glucocorticoid-mediated antiinflammatory activity in the in vitro U937 cell model of LPS-induced IL-1 induction and found to be devoid of glucocorticoid activity. Angiostatic steroids which lack glucocorticoid activity should be attractive drug candidates for treating ocular neovascular disease.

Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents; Chick Embryo; Choroid; Choroidal Neovascularization; Cornea; Disease Models, Animal; Dose-Response Relationship, Drug; Glucocorticoids; Humans; Hydrocortisone; In Vitro Techniques; Interleukin-1; Lipopolysaccharides; Neovascularization, Pathologic; Rabbits; Steroids; U937 Cells

To evaluate the antiangiogenic potential of topical ophthalmic formulations of the novel angiostatic steroids AL-3789 and AL-4940, using a rabbit model of corneal neovascularization.. Neovascularization was induced in the rabbit cornea by surgical implantation of a standard ethylene vinyl acetate copolymer (Elvax-40) pellet containing 1 microg lipopolysaccharide. Coded formulations of the control vehicle or the following test agents were administered in prevention and intervention treatment protocols: 1% formulations of AL-3789, AL-4940, and cortisol acetate as a positive drug control. Three doses of AL-3789 (0.01%, 0.1%, and 1%) were also evaluated in a prevention treatment protocol. Corneal responses were monitored throughout a 2-week treatment period, and 1 week after the last treatment dose. Observations included quantitative measurement of the area of new blood vessel growth and qualitative assessment of cellular infiltrate and edema. All treatments and observations were performed in a double-masked manner.. All tested formulations, except the vehicle and the 0.01% AL-3789 preparation, significantly inhibited corneal neovascularization and other lipopolysaccharide-induced responses in the various treatment protocols employed. AL-4940, the free alcohol form of AL-3789, was slightly less effective than cortisol acetate or AL-3789. The extent of inhibition of the angiogenic response by the 1% and 0.1% AL-3789 suspensions ranged from 76% to 100% 1 week after the last treatment.. The antiangiogenic steroid AL-3789 may be a therapeutically useful angiostatic agent for corneal neovascularization and potentially could be effective in other ocular neovascular diseases.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Cornea; Corneal Neovascularization; Disease Models, Animal; Double-Blind Method; Drug Delivery Systems; Female; Hydrocortisone; Lipopolysaccharides; Male; Ophthalmic Solutions; Polyvinyls; Rabbits; Salmonella typhimurium