Intravitreal injection animal studies

Administration is by direct injection of 0.05 ml product into the eye (intravitreal injection), initially once every 2 weeks and subsequently once every 4 weeks. Animal studies (rabbits) indicated that the product is cleared from the eye over the course of 7-10 days, with direct nuclease-mediated metabolism representing the primary route of elimination. The most commonly observed side effect is ocular inflammation, which typically occurs in one in every four patients. 

Safety. Animal studies have shown that ranibizumab is a safe agent for intravitreal injection. In cynomolgus monkeys, intravitreal injections of 500 pg of ranibizumab at two-week intervals in a laser-induced CNV model (13) or in normal monkey eyes did not show any significant adverse effects (14). However, mild side effects of the injections were seen. All eyes treated with ranibizumab developed acute anterior chamber inflammation within 24 hours of the first intravitreal injection (13). In contrast, eyes injected with vehicle alone showed minimal or no inflammation. The inflammation resolved within one week, and the inflammatory response was less pronounced after subsequent intravitreal ranibizumab injections. Also, animal studies have shown that ranibizumab has no effect on electroretinography, including visually evoked potentials. 

The use of intravitreal corticosteroids was first popularized by Machemer in 1979 (33) in an effort to halt cellular proliferation after retinal detachment surgery, and Graham (34), McCuen (35), Tano (36), and others have studied its use in both animal models and humans. In contrast to other corticosteroids with short half-lives following intravitreal injection, triamcinolone acetonide is an effective and well-tolerated (35,37) agent for intravitreal injection in conditions such as uveitis (38,39), macular edema secondary to ocular trauma or retinal vascular disease (40), proliferative diabetic retinopathy (41), intraocular proliferation such as proliferative vitreoretinopathy (42), and choroidal neovascularization from AMD (43,44). 

Prior studies have demonstrated the promise of growth factors, neurotrophic factors, and cytokines given by intravitreal injection in short-term animal experiments as potential therapy for RP (15,27,28,30). Among these, ciliary neurotrophic factor (CNTF) is effective (15). Unfortunately, the chronic nature of the disease and the adverse effects associated with repeated short-duration intraocular administration mitigates the use of CNTF by this delivery method. 

The efficacy of RA in PVR has been evaluated in animal models. A single intravitreal injection of RA used in conjunction with silicone oil reduces the incidence of traction retinal detachment (40). Use of microsphere encapsulation of RA to prolong the intravitreal half-life reduced the incidence of PVR in the rabbit model by 64% (41). Intravitreal RA suspended in 1% sodium hyaluronate has also been studied in a rabbit model of PVR and has similar inhibitory effect on PVR progression. The authors suggested that in cases in which silicone oil was not necessary, sodium hyaluronate could be used as an RA vehicle, though transient elevations of intraocular pressure could be expected (42). 

As discussed previously, corticosteroids downregulate VEGF production in experimental models and possibly reduce breakdown of the blood retinal barrier (15,16). Similarly, corticosteroids have antiangiogenic properties possibly due to attenuation of the effects of VEGF (20,21). These properties of steroids are commonly used. Clinically, triamcinolone acetonide is used locally as a periocular injection to treat cystoid macular edema secondary to uveitis or as a result of intraocular surgery (22,23). In animal studies, intravitreal triamcinolone acetonide has been used to prevent proliferative vitreoretinopathy and retinal neovascularization (24—27). Intravitreal triamcinolone acetonide has been used clinically to treat proliferative vitreoretinopathy and choroidal neovascularization (28-31). 

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