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Retina: Fenghua Wang, Zhiliang Wang, Xiaodong Sun, Fang Wang, Xun Xu, and Xi Zhang Safety and Efficacy of Dispase and Plasmin in Pharmacologic Vitreolysis Invest. Ophthalmol. Vis. Sci. 2004; 45: 3286-3290 [Abstract] [Full text] [PDF]

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Pharmacologic Vitreolysis

Arnd Gandorfer   (8 April 2005)

Author Response: Pharmacologic Vitreolysis

Fenghua Wang   (8 April 2005)

Pharmacologic Vitreolysis 8 April 2005
Arnd Gandorfer Send letter to journal: Re: Pharmacologic Vitreolysis arnd.gandorfer{at}ak-i.med.uni-muenchen.de Arnd Gandorfer	We read with interest the article by Dr. Wang and colleagues on the safety and efficacy of dispase and plasmin in pharmacologic vitreolysis.1 We appreciate the critical approach to test different enzyme concentrations in an animal model by assessing both morphological and functional changes of the retina, and we congratulate the authors on their work. We would like to comment on some aspects of Dr. Wang's article, as this may enhance our limited knowledge of enzymatically induced posterior vitreous detachment (PVD). Dispase has previously been shown to induce retinal hemorrhages and proliferative vitreoretinopathy in rabbit and human eyes.2 It would be interesting to know whether the authors observed any signs of proliferative vitreoretinopathy in their series. As Dr. Wang and colleagues pointed out, dispase acts on type IV collagen, which is the main structural component of basement membranes including the internal limiting membrane of the retina, and it is not surprising that damage to the inner limiting membrane has been observed following treatment with dispase. It is unclear, however, whether dispase also acts on retinal layers deeper than the vitreoretinal interface, such as the nerve fiber layer and the ganglion cell layer. From Figures 4B and 4C of the present article, one can get the impression that the inner limiting membrane is completely absent, and deeper retinal layers are damaged as well. Regarding plasmin enzyme and the inflammatory response reported in the current series, we would like to ask the authors from which species the plasmin they used was derived. Species-related differences in the molecular structure of the enzyme may influence not only the safety of the drug in terms of an acute inflammatory reaction but also the efficacy of PVD induction. Moreover, it would be interesting to know about the severity of inflammation and whether there was a correlation between the inflammatory response and ERG changes. Ideally, pharmacologic vitreolysis is a combination of PVD induction and liquefaction of the vitreous gel.2 Microplasmin has been shown to separate the vitreous cortex from the retina and to liquefy the vitreous gel (unpublished poster, presented at the 5th International Symposium on Ocular Pharmacology and Therapeutics (ISOPT), Monte Carlo, 2004).4 May we ask Dr. Wang and coworkers whether they observed any signs of vitreous liquefaction in their series, as this may further indicate the efficacy of plasmin enzyme? Finally, we would like to encourage the authors to continue their work on pharmacologic vitreolysis and potential untoward effects on the retina, as these data are essential for the development of pharmacologic vitreolysis in humans. Arnd Gandorfer and Anselm Kampik University Eye Hospital Munich, Munich, Germany References 1. Wang F, Wang Z, Sun X, Wang F, Xun X, Zhang X. Safety and efficacy of dispase and plasmin in pharmacologic vitreolysis. Invest Ophthalmol Vis Sci. 2004;45:3286-3290. 2. Jorge R, Oyamaguchi EK, Cardillo JA, Gobbi A, Laicine EM, Haddad A. Intravitreal injection of dispase causes retinal hemorrhages in rabbit and human eyes. Curr Eye Res. 2003;26:107-112. 3. Sebag J. Is pharmacologic vitreolysis brewing? Retina. 2002;22:1-3. 4. Gandorfer A, Rohleder M, Sethi C, et al. Posterior vitreous detachment induced by microplasmin. Invest Ophthalmol Vis Sci. 2004;45:641-647.
Author Response: Pharmacologic Vitreolysis 8 April 2005
Fenghua Wang Send letter to journal: Re: Author Response: Pharmacologic Vitreolysis Fenghua{at}seeeye.org Fenghua Wang	We appreciate Dr. Gandorfer and Dr. Kampik's interest in our article and thank them for their thoughtful comments. For the question on proliferative vitreoretinopathy (PVR) induced by dispase, we did observe PVR when we extended the observation time to 1 month after injecting 0.05U (or more) dispase. In the eyes that received high dose dispase, the dense vitreous hemorrhage was followed by membrane formation and tractional retinal detachment. Dispase apparently can damage the retina. As Figure 3B of our paper1 showed, after the injection of dispase, the inner limiting membrane was absent, the retinal ganglion cells and bipolar cells were injured, while the outer layer of retina was not substantially affected. We think that these events are related to the fact that dispase can digest the extra- cellular matrix of the inner retinal layers. We used human plasmin in our experiments. There was obvious inflammation, including anterior chamber exudation and vitreous haze. However, there was no evidence that the inflammation induced permanent retinal damage in our experiments. The ERG responses of the plasmin group were slightly reduced, but these reductions were not significantly different (Table 3) from those before the injection. In our experiments, we also observed partial vitreous liquefaction in plasmin injected eyes which were extracted 7 days after operation. But as has already been shown, inflammation can result in vitreous liquefaction. We do not regard this as evidence that plasmin injection directly induces vitreous liquefaction. It had been a question for us whether it was plasmin itself or the inflammation that induced the posterior vitreous detachment (PVD). But the facts that PVD appeared before the inflammation and that inflammation alone only induced partial PVD seem to support the conclusion that plasmin itself can induce PVD. We have explored another method in our latest experiments: combining plasmin and hyaluronidase. Since hyaluronidase can liquefy the vitreous gel, plasmin can fully act on the vitreous-retina interface and induce complete PVD with a much lower dose. We believe that plasmin and microplasmin have a promising future in pharmacologic vitreolysis.2 However, the difference between the human eye and animal eyes of different species and the difference between normal and pathological human eyes should be more carefully considered before this method is used clinically. Xi Zhang Fenghua Wang Xiaodong Sun Zhiliang Wang Shanghai First People's Hospital, Shanghai, People's Republic of China References 1. Wang F, Wang Z, Sun X, Wang F, Xu X, and Zhang X. Safety and efficacy of dispase and plasmin in pharmacologic vitreolysis. Invest Ophthalmol Vis Sci. 2004;45:3286-3290. 2. Gandorfer A, Rohleder M, Sethi C, et al. Posterior vitreous detachment induced by microplasmin. Invest Ophthalmol Vis Sci. 2004;45:641-647.