EVALUATION OF RETINAL TOXICITY AND LIPOSOME ENCAPSULATION OF THE ANTI-CMV DRUG 2'-NOR-CYCLIC GMP

Purpose. Human cytomegalovirus (HCMV) is an important pathogen in the immunocompromised patient. CMV retinitis is a leading cause of blindne ss in patients with AIDS. Ganciclovir and foscarnet are currently the treatments being used for this retinitis, but they both have major tox icities when used systemically. Intravitreal therapy with ganciclovir has been used in some patients who cannot tolerate systemic treatment. The major problem with this modality is the necessity for administrat ion of between 1 and 3 intravitreal injections per eye per week. 2'-no r-cyclic GMP is a nucleotide analog, a cyclic phosphate derivative of ganciclovir. Neutral salts of the compound are extremely water soluble , and the charged phosphate group at neutral pH make it an ideal candi date for encapsulation into a multivesicular liposome system. Methods. The authors evaluated the retinal toxicity of the diethanolammonium s alt 2'-nor-cyclic GMP by using electroretinographic, morphologic, and ophthalmoscopic techniques after intravitreal injections in rabbit eye . Results. The intraocular therapeutic index for 2'-nor-cyclic GMP is 20. At the 10 mug dose, electroretinogram, ophthalmoscopic examination , and both light and electron microscopy revealed no abnormalities. To xicity was evident at 50 mug and higher doses with ERG changes (loss o f amplitude) and retinal pathology that varied from vacuolization of t he retinal pigment epithelium and loss of height of the outer photorec eptor segment to loss of the entire outer retina. In addition, an in v itro drug release half-life of 1,000 hours (more than 75 times that of ganciclovir) was found for 2-nor-cyclic GMP in liposome, which may be able to be exploited in the therapy of patients with CMV retinitis un able to tolerate toxic systemic therapy. Conclusion. The anti-CMV drug , 2-nor-cyclic GMP, may be promising for intravitreal injection, parti cularly if encapsulated into liposomes.