INTRAVITREAL SUSTAINED-RELEASE CYCLOSPORINE IN THE TREATMENT OF EXPERIMENTAL UVEITIS

Objective: Uveitis often is a chronic disease requiring long-term medi cal therapy. Despite treatment, the disease may be difficult to contro l and may produce serious, vision-threatening ocular complications. In this study, the authors determined whether an intravitreal cyclospori ne-sustained delivery device was effective in the treatment of ocular inflammation in a rabbit model of uveitis. Methods: New Zealand White rabbits were immunized subcutaneously with Mycobacterium tuberculosis H37Ra antigen. Fourteen days later, sustained-release cyclosporine dev ices were implanted into the vitreous cavity of the right eye of exper imental rabbits. Control animals received sham devices. Seven days aft er device implantation, rabbits were challenged with an intravitreal i njection of tuberculin antigen. To simulate chronic inflammation with exacerbations, some animals were rechallenged with intravitreal antige n on day 21 after device implantation. Inflammation was assessed clini cally by a masked observer who graded anterior chamber cells, flare, c orneal neovascularization, iris congestion, and vitreous opacity daily until day 7 and on day 13 after the initial intravitreous challenge, and on days 1 and 2 after the rechallenge, Retinal function was evalua ted by electroretinography. Animals were killed 3, 6, 8, and 14 days a fter the initial intravitreal challenge and on the second day after re challenge for aqueous leukocyte count, protein measurement, and histol ogic examination. The number of aqueous and peripheral blood prolifera ting lymphocytes and the subset of CD4(+) T cells were determined by f low cytometry. High-performance liquid chromatography was used to meas ure cyclosporine A levels in vitreous and peripheral blood. Light micr oscopy was used to evaluate the eyes histopathologically. Results: By clinical criteria, treated eyes had significantly less inflammation th an untreated eyes. The number of aqueous cells and protein concentrati on determined quantitatively paralleled the clinical assessment of ant erior chamber cells and flare. The electroretinography B-wave was depr essed significantly in untreated eyes compared with that of treated ey es (P < 0.02). Histopathologic examination results showed marked infla mmation and tissue disorganization in untreated eyes, whereas cyclospo rine-treated eyes had preserved architecture and greatly reduced infla mmatory cells. Intravitreal cyclosporine remained at therapeutic level s for at least 6 months after intravitreal device implantation, wherea s blood levels were low to nondetectable. Conclusions: The intravitrea l cyclosporine A device effectively suppresses ocular inflammation in a rabbit model of uveitis. This device may be useful in the treatment of patients with severe chronic uveitis who are intolerant to currentl y available therapies.