In recent times, the use of intraocular drugs has become frequent in ophthalmology, in particular in the treatment of retinal diseases. Such treatments are most often off-label use of compounds that have been developed for systemic use, not as primary intraocular agents. The modern history of this off-label use began with drugs for endophthalmitis and then progressed to anticytomegaloviral drugs for human immunodeficiency virus infection‐associated acute retinal necrosis syndrome. More recently, triamcinolone has come into widespread use for patients with macular edema from a variety of causes. In addition to therapeutic intravitreal agents, intravitreal drugs have become popular as surgical adjuvants to pars plana vitrectomy. Compounds such as ICG, trypan blue, and triamcinolone have been used to assist visualization of the internal limiting membrane, epiretinal membranes, and vitreous cortex and have been widely considered useful adjuncts to vitreoretinal surgery. One of the problems with the use of intraocular drugs, particularly if not primarily developed for this purpose, is the conflicting publications in the scientific literature about their safety. For example, a search of PubMed for the use of ICG in vitrectomy surgery returned 146 papers published in the area. These included clinical studies in patients, in vivo studies in animals, and in vitro studies of the dye in tissue culture. The conclusions were widely conflicting, with some finding that ICG is safe and others that it is toxic. Some investigators have decided that if the retina is intact (i.e., no macular hole), then the use of ICG is safe, but if the substance comes in contact with the retinal pigment epithelium (RPE), toxicity ensues. The multiple methods of evaluation of drugs or compounds to be used in the eye lead to much confusion about their toxicity. For example, ICG is widely used to aid in visualizing the internal limiting membrane of the retina so that it can be removed in eyes with macular holes and macular edema, yet there is controversy regarding its potential for toxicity. In tissue culture systems and in some studies in which in vivo evaluation systems were used, the dye has been found to be either safe or toxic at similar concentrations. 1,2 Some investigators have attributed toxicity to the osmolarity of the solution and have suggested that isosmolar preparations of ICG are not toxic. Others have concluded that toxicity may be light dependent, and still others have concluded that the compound is toxic only to the RPE cells and not the retina. We are in the uncomfortable position of having a dye in use as a surgical adjuvant whose safety seems to be controversial. Standardized methods of evaluation that are universally acceptable seem to be lacking. One of the problems in evaluating such drugs and compounds is the lack of a standard agreed-on methodology. Certainly tissue culture is one way to evaluate such drugs, but the results may be misleading. The intraocular milieu is complex and difficult to replicate in a tissue culture system. For example, testing of the toxicity of drugs injected into the vitreous using RPE cell lines may be irrelevant, as most of the drug is in contact with the retinal surface, not the RPE. It is difficult to replicate the clinical situation in vivo in tissue culture, and the relevancy of such results is questionable. Using in vivo systems or tissue culture cell lines, several groups have made efforts to evaluate the effect of triamcinolone. 3‐7 One problem is that triamcinolone is water insoluble. When injected into the human vitreous cavity, the compound may not even directly contact the retinal surface, because much of it is suspended in the liquid or formed vitreous. The effect of the drug on the retina has been reported by some observers to be beneficial in cases of macular edema due to several different diseases. Such an effect is presumably mediated by the solubilized fraction of drug; the portion of triamcinolone crystals that dissolve in the vitreous fluid. It is difficult to know if, in vivo, triamcinolone crystals are in equilibrium, what the soluble fraction of triamcinolone is in the vitreous, and precisely what concentration of soluble drug is available to
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