Filtration surgery is often required in many patients whose glaucoma has failed to be controlled by medical means. This surgery differs from other surgical procedures in that the fistula is expected to heal minimally or not at all in order to maintain filtration. Therefore, the advent of pharmacologic means to retard or control wound healing has become a most promising approach to improve the surgical outcome in these patients. In the preliminary experiments, an improved experimental model for the study of the use of wound healing retardants in filtration surgery was developed and a new hypothesis for the control of wound healing at the limbus was derived. According to the proposal, the vascularized limbal tissues are most important to the scar formation process following filtration surgery; therefore, if the healing process is controlled within these tissues, the fistula should remain patent. A liposomal delivery system was selected to assure that the drug could be delivered to a well-specified area and the potent, liposomal dependent drug, 5-fluoroorotate (L5F0) was selected as the wound healing retardant. Results of the applicant's and preliminary studies indicated that their hypothesis may be correct and that L5F0 is a promising agent which merits further study. The goal of this proposal is to evaluate by quantitative means at least five anti-scarring agents and to select the most efficacious and safe for a possible clinical trial. Specifically, the Investigators plan to evaluate L5F0, heparin, daunomycin, alpha-transferrin immunotoxin and glucocorticoids. Posterior lip sclerectomies would be created surgically in animal experiments. Initially, L5F0 would be completely studied to develop appropriate protocols and standards. Subsequently, the other drugs would be employed and compared with L5F0. The experimental design comprises a series of quantitative studies of normal wound healing followed by comparisons with the use of wound healing retardants. The data would include clinical measurements of IOP and outflow facility and quantitative assessment of fibroplasia and fibrillogenesis in tissues by morphometric and biochemical means. Through these comparisons, determinations of the best drug administration schedule (time, dose, frequency) would be made. These five agents would also be compared in their ability to maintain patency of a fistula created with a laser instrument. In addition, whether there is a """"""""secondary"""""""" healing response when a Molteno device begins to drain aqueous humor and whether wound healing retardants could be used to prevent such a response would be investigated. The results of these experiments should offer new techniques for the glaucoma surgeon to control the development of scars and to ensure a greater success after filtration surgery.
