title: The retinal tolerance to bevacizumab in co-application with a recombinant tissue plasminogen activator.
abstract: OBJECTIVE
  To investigate the retinal toxicity of bevacizumab in co-application with a commercially available recombinant tissue plasminogen activator (rt-PA), and to facilitate a new therapeutic concept in the treatment of massive subretinal haemorrhage caused by neovascular age-related macular degeneration (AMD).
  
  
  METHODS
  Isolated bovine retinas were perfused with an oxygen-preincubated nutrient solution. The electroretinogram (ERG) was recorded as a transretinal potential using Ag/AgCl electrodes. Bevacizumab (0.25 mg/ml) and rt-PA (20 microg/ml) were added to the nutrient solution for 45 min. Thereafter, the retina was reperfused for 60 min with normal nutrient solution. Similarly, the effects of rt-PA (20 microg/ml, 60 microg/ml and 200 mug/ml) on the a- and b-wave amplitudes were investigated. The percentages of a- and b-wave reduction during application and at washout were calculated.
  
  
  RESULTS
  During application of bevacizumab (0.25 mg/ml) in co-application with 20 microg/ml (rt-PA), the ERG amplitudes remained stable. The concentrations of rt-PA alone (20 microg/ml and 60 microg/ml) did not induce significant reduction of the b-wave amplitude. In addition, 20 microg/ml rt-PA did not alter the a-wave amplitude. However, 60 microg/ml rt-PA caused a slight but significant reduction of the a-wave amplitude. A full recovery was detected for both concentrations during the washout. At the highest tested concentration of 200 microg/ml rt-PA, a significant reduction of the a- and b-wave amplitudes was provoked during the exposure. The reduction of ERG amplitudes remained irreversible during the washout.
  
  
  CONCLUSIONS
  The present study suggests that a subretinal injection of 20 microg/ml rt-PA in co-application with bevacizumab (0.25 mg/ml) for the treatment of massive subretinal haemorrhage seems possible. This is a safety study. Therefore, we did not test the clinical effectiveness of this combined treatment.
authors: Department of Ophthalmology, University of Tuebingen, Schleichstr. 12-16, D-72076 Tuebingen, Germany. matthias.lueke@med.uni-tuebingen.de
authors: Matthias
authors: M
authors: Lüke
authors: Kai
authors: K
authors: Januschowski
authors: Max
authors: M
authors: Warga
authors: Julia
authors: J
authors: Beutel
authors: Martin
authors: M
authors: Leitritz
authors: Faik
authors: F
authors: Gelisken
authors: Salvatore
authors: S
authors: Grisanti
authors: Toni
authors: T
authors: Schneider
authors: Christoph
authors: C
authors: Lüke
authors: Karl Ulrich
authors: KU
authors: Bartz-Schmidt
authors: Peter
authors: P
authors: Szurman
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002417:Cattle; D004338:Drug Combinations; D005343:Fibrinolytic Agents / Q000009:adverse effects*; D011994:Recombinant Proteins / Q000009:adverse effects; D012160:Retina / Q000187:drug effects*; D012166:Retinal Hemorrhage / Q000139:chemically induced*; D046509:Tissue Culture Techniques; D010959:Tissue Plasminogen Activator / Q000009:adverse effects*
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004338:Drug Combinations; D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D000068258:Bevacizumab; D010959:Tissue Plasminogen Activator