title: Safety profile of the intravitreal streptokinase-plasmin complex as an adjunct to vitrectomy in the rabbit.
abstract: BACKGROUND
  The generation of an atraumatic posterior vitreous detachment (PVD), a common goal in vitreoretinal surgery, is a challenge, particularly in children and young trauma patients. Plasmin has been proposed as an adjunct to vitrectomy to enzymatically 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 streptokinase-plasmin in rabbits.
  
  
  METHODS
  Plasminogen was isolated from human plasma by affinity chromatography, followed by activation with streptokinase (1:1), to generate the streptokinase-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 performed 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 medullary rays in the late follow-up. Electroretinograms (ERGs) of vitrectomized control eyes showed the following changes from preoperative values: 48 h, a-wave -11.10% [no 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: 48 h: 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.
  
  
  CONCLUSIONS
  Streptokinase-plasmin doses up to 3 AU were found to be safe when injected into rabbit eyes followed by vitrectomy.
authors.affiliation: Department of Ophthalmology, RWTH Aachen University, Pauwelsstrasse 30, 52057, Aachen, Germany. mah30@gmx.de
authors.forename: M
authors.initials: M
authors.lastname: Hermel
authors.forename: M
authors.initials: M
authors.lastname: Mahgoub
authors.forename: T
authors.initials: T
authors.lastname: Youssef
authors.forename: M I
authors.initials: MI
authors.lastname: Azrak
authors.forename: H
authors.initials: H
authors.lastname: Raza
authors.forename: C
authors.initials: C
authors.lastname: Alldredge
authors.forename: M
authors.initials: M
authors.lastname: Trese
authors.forename: G A
authors.initials: GA
authors.lastname: Williams
authors.forename: M
authors.initials: M
authors.lastname: Hartzer
mesh_terms: D000818:Animals; D002846:Chromatography, Affinity; D003131:Combined Modality Therapy; D004338:Drug Combinations; D004596:Electroretinography; D006801:Humans; D007267:Injections; D010775:Photic Stimulation; D010958:Plasminogen / Q000008:administration & dosage* / Q000009:adverse effects / Q000302:isolation & purification; D011817:Rabbits; D012160:Retina / Q000187:drug effects / Q000502:physiology; D013300:Streptokinase / Q000008:administration & dosage* / Q000009:adverse effects; D014821:Vitrectomy / Q000009:adverse effects / Q000379:methods*; D014822:Vitreous Body / Q000187:drug effects; D020255:Vitreous Detachment / Q000601:surgery*
chemical_list: D004338:Drug Combinations; C049423:streptokinase-plasminogen complex; D010958:Plasminogen; D013300:Streptokinase