Graefe’ s Arch Clin Exp Ophthalmol (2006) 244: 996–1002 DOI 10.1007/s00417-005-0159-4 LABORATORY INVESTIGATION M. Hermel M. Mahgoub T. Youssef M. I. Azrak H. Raza C. Alldredge M. Trese G. A. Williams M. Hartzer Received: 22 May 2005 Revised: 30 August 2005 Accepted: 19 September 2005 Published online: 20 December 2005 # Springer-Verlag 2005 Safety profile of the intravitreal streptokinase–plasmin complex as an adjunct to vitrectomy in the rabbit Abstract Background: The genera- tion of an atraumatic posterior vitreous detachment (PVD), a common goal in vitreoretinal surgery, is a challenge, particularly in children and young trau- ma patients. Plasmin has been proposed as an adjunct to vitrectomy to enzy- matically generate a PVD. Low doses of streptokinase-activated plasmin were tested in human pilot studies. This dose- escalation study assesses the safety range of intravitreal human streptoki- nase–plasmin in rabbits. Methods: Plasminogen was isolated from human plasma by affinity chromatography, followed by activation with streptoki- nase (1:1), to generate the streptoki- nase–plasmin complex. Enzyme doses from 0.1–7 activity units (AU, in 0.1 ml) were injected into the mid-vitreous of 35 eyes; six control eyes were injected with balanced salt solution (BSS, 0.1 ml). Thirty minutes after injection, a two-port vitrectomy was performed. Fundus and slit lamp examinations were performed on days 1 and 7. On days 2 and 7 bright flash electroretinography was per- formed and compared with preoperative recordings. Some animals receiving higher doses of streptokinase–plasmin (1–7 AU) were followed clinically and with electroretinography for up to 9 months. Results: A mild-to-moderate inflammatory response was seen in both control and plasmin-treated eyes on day 1 but had disappeared completely by day 7 in most eyes. In the 7 AU group, inflammation was stronger and more protracted. Two of three eyes from this group developed wrinkling of the medullary rays; one of them showed discoloration and traction at the med- ullary rays in the late follow-up. Elec- troretinograms (ERGs) of vitrectomized control eyes showed the following changes from preoperative values: 48 h, a-wave -11.10% [not significant (n.s.)], b-wave -14.62% (P=0.046); 7 days, a-wave +9.18% (n.s.), b-wave +11.69% (n.s.). For the enzyme-treated eyes: 48h, a-wave -20.43% (P<0.001), b-wave -9.57% (P<0.001); 7 days, a-wave -14.21% (P<0.001), b-wave +2.48% (P<0.001). There was no evidence of dose- dependent ERG changes in enzyme- treated eyes at doses up to 5 AU. Groups of up to 3 AU were investigated by light and transmission electron microscopy, without evidence of toxicity. Conclusion: Streptokinase–plasmin doses up to 3 AU were found to be safe when injected into rabbit eyes followed by vitrectomy. Keywords Vitrectomy . Plasmin drug effects . Toxicology . Enzyme . Rabbit This work was presented in part at the 74th Annual Meeting of the Association for Research in Vision and Ophthalmology 2002. M. Hermel (*) Department of Ophthalmology, RWTH Aachen University, Pauwelsstrasse 30, 52057 Aachen, Germany e-mail: mah30@gmx.de Tel.: +49-241-8883793 Fax: +49-241-8082408 M. Hermel . M. I. Azrak . H. Raza . C. Alldredge . M. Trese . G. A. Williams Associated Retinal Consultants, Royal Oak, MI, USA M. Mahgoub . T. Youssef Department of Ophthalmology, Ain Shams University, Cairo, Egypt M. Hartzer NuVue Technologies, Keene, NH, USA