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Toxic Effect of Fluorouracil on the Rabbit Retina: Reply
534
AMERICAN JOURNAL OF OPHTHALMOLOGY REFERENCES
1. Lewis, G. P., Guerin, C. J., Erickson, P. A., and Stern, W. H.: Reversible toxicity of 5-FU treatment for proliferative vitreoretinopathy. ARVO Abstracts. Supplement to Invest. Ophthalmol. Vis. Sci. Philadelphia, J. B. Lippincott, 1983, p. 241. 2. Stern, W. Hoo Guerin, C. J., Erickson, P. A., Anderson, D. H., and Fisher, S. K: Ocular toxicity of fluorouracil after vitrectomy. Am. J. Ophthalmol. 96:43, 1983. 3. Heuer, D. K, Parrish, R. K, Gresesel, M. G., Hodapp, Eoo Palmberg, P. F., and Anderson, D. R.: 5-Fluorouracil and glaucoma filtering surgery. II. A pilot study. Ophthalmology. In press. 4. Rootman, J., Tisdall, J., Gudauskas, G., and Ostry, A.: Intraocular penetration of subconjunctivallv administered 14C-fluorouracil in rabbits. Arch. Ophthalmol, 97:2375, 1979.
Reply EDITOR:
Unfortunately the work of Lewis and associates'< was not available to us while we were preparing our article. Rootman and associates" Figure 3 suggests that 10% of the injected dose was 1,250 ug, On the basis of the data in Tables 1 and 2, each eye received 12.5 mg of fluorouracil and no eye received 18.75 mg. In the vitrectomized rabbit eye after fluid-gas exchange, the fluorouracil accumulates in the lower portion of the globe during gas absorption. Thus, the electroretinogram may not be affected because it represents the overall response of the entire retina. Combined lensectomy and vitrectomy increases the circulation of low-viscosity fluid in the vitreous cavity and increases the access of intravitreally administered drug to the outflow channels in the anterior chamber. The mean vitreous concentration was thought to be lower than 3.14 x 104 glml (initial maximum concentration) in the experiment of Lewis and associates. The retina tolerates much higher concentrations for short periods. Their data and our data suggest that the criticial concentration is between 104 and 15 glml. Binder and associates" observed retinal and vascular changes in a large number of nonvitrec-
APRIL, 1984
tomized eyes given 1 mg of fluorouracil intravitreally. They observed that the optic disk was completely pale and the retinal vessels could not be seen after four weeks in some rabbits given 5 mg of fluorouracil. We also found some evidence of a toxic effect on the pigment epithelium (R. Yamakawa, N. Nao-i, K. Koizumi, M. Matsumura, N. Ogino, and Y. Honda, unpublished data). Our point is that fluorouracil has an inadequate margin of safety. Detached or damaged human retinas may be much weaker than intact rabbit retinas. We believe this drug should be used only when the benefit of administration excceeds these considerable risks. NOBUHISA NAO-I, M.D. YOSHIHITO HONDA, M.D. Kyoto, Japan REFERENCES 1. Lewis, G. P., Guerin, C. J., Erickson, P. A., and Stern, W. H.: Reversible toxicity of 5-FU treatment for proliferative vitreoretinopathy, ARVO Abstracts. Supplement to Invest. Ophthalmol, Vis. Sci. Philadelphia, J. B. Lippincott, 1983, p. 241. 2. Stem, W. H., Guerin, C. J., Erickson, P. A., Lewis, G. P., Anderson, D. H., and Fisher, S. K: Ocular toxicity of fluorouracil after vitrectomy. Am. J. Ophthalmol. 96:43, 1983. 3. Rootman, J., Tisdall, J. Gudauskas, G., and Ostry, A.: Intraocular penetration of subconjunctivally administered 14C-fluorouracil in rabbits. Arch. Ophthalmol. 97:2375, 1979. 4. Binder, S., Riss, B., Skorpik, C., and Kulnig, W.: Inhibition of experimental intraocular proliferation with intravitreal 5-fluorouracil. Graefes Arch. Clin. Exp. Ophthalmol. 221:126, 1983.
BOOK REVIEWS Edited by H. Stanley Thompson, M. D.
Radial Keratotomy. Edited by Donald Sanders. Thorofare, New Jersey, SLACK, Inc., 1984. Softcover, 126 pages. $24.50 Reviewed by LAWRENCE W. HIRST St. Louis, Missouri
AMERICAN JOURNAL OF OPHTHALMOLOGY REFERENCES
1. Lewis, G. P., Guerin, C. J., Erickson, P. A., and Stern, W. H.: Reversible toxicity of 5-FU treatment for proliferative vitreoretinopathy. ARVO Abstracts. Supplement to Invest. Ophthalmol. Vis. Sci. Philadelphia, J. B. Lippincott, 1983, p. 241. 2. Stern, W. Hoo Guerin, C. J., Erickson, P. A., Anderson, D. H., and Fisher, S. K: Ocular toxicity of fluorouracil after vitrectomy. Am. J. Ophthalmol. 96:43, 1983. 3. Heuer, D. K, Parrish, R. K, Gresesel, M. G., Hodapp, Eoo Palmberg, P. F., and Anderson, D. R.: 5-Fluorouracil and glaucoma filtering surgery. II. A pilot study. Ophthalmology. In press. 4. Rootman, J., Tisdall, J., Gudauskas, G., and Ostry, A.: Intraocular penetration of subconjunctivallv administered 14C-fluorouracil in rabbits. Arch. Ophthalmol, 97:2375, 1979.
Reply EDITOR:
Unfortunately the work of Lewis and associates'< was not available to us while we were preparing our article. Rootman and associates" Figure 3 suggests that 10% of the injected dose was 1,250 ug, On the basis of the data in Tables 1 and 2, each eye received 12.5 mg of fluorouracil and no eye received 18.75 mg. In the vitrectomized rabbit eye after fluid-gas exchange, the fluorouracil accumulates in the lower portion of the globe during gas absorption. Thus, the electroretinogram may not be affected because it represents the overall response of the entire retina. Combined lensectomy and vitrectomy increases the circulation of low-viscosity fluid in the vitreous cavity and increases the access of intravitreally administered drug to the outflow channels in the anterior chamber. The mean vitreous concentration was thought to be lower than 3.14 x 104 glml (initial maximum concentration) in the experiment of Lewis and associates. The retina tolerates much higher concentrations for short periods. Their data and our data suggest that the criticial concentration is between 104 and 15 glml. Binder and associates" observed retinal and vascular changes in a large number of nonvitrec-
APRIL, 1984
tomized eyes given 1 mg of fluorouracil intravitreally. They observed that the optic disk was completely pale and the retinal vessels could not be seen after four weeks in some rabbits given 5 mg of fluorouracil. We also found some evidence of a toxic effect on the pigment epithelium (R. Yamakawa, N. Nao-i, K. Koizumi, M. Matsumura, N. Ogino, and Y. Honda, unpublished data). Our point is that fluorouracil has an inadequate margin of safety. Detached or damaged human retinas may be much weaker than intact rabbit retinas. We believe this drug should be used only when the benefit of administration excceeds these considerable risks. NOBUHISA NAO-I, M.D. YOSHIHITO HONDA, M.D. Kyoto, Japan REFERENCES 1. Lewis, G. P., Guerin, C. J., Erickson, P. A., and Stern, W. H.: Reversible toxicity of 5-FU treatment for proliferative vitreoretinopathy, ARVO Abstracts. Supplement to Invest. Ophthalmol, Vis. Sci. Philadelphia, J. B. Lippincott, 1983, p. 241. 2. Stem, W. H., Guerin, C. J., Erickson, P. A., Lewis, G. P., Anderson, D. H., and Fisher, S. K: Ocular toxicity of fluorouracil after vitrectomy. Am. J. Ophthalmol. 96:43, 1983. 3. Rootman, J., Tisdall, J. Gudauskas, G., and Ostry, A.: Intraocular penetration of subconjunctivally administered 14C-fluorouracil in rabbits. Arch. Ophthalmol. 97:2375, 1979. 4. Binder, S., Riss, B., Skorpik, C., and Kulnig, W.: Inhibition of experimental intraocular proliferation with intravitreal 5-fluorouracil. Graefes Arch. Clin. Exp. Ophthalmol. 221:126, 1983.
BOOK REVIEWS Edited by H. Stanley Thompson, M. D.
Radial Keratotomy. Edited by Donald Sanders. Thorofare, New Jersey, SLACK, Inc., 1984. Softcover, 126 pages. $24.50 Reviewed by LAWRENCE W. HIRST St. Louis, Missouri